6-substituted nicotinamide derivatives as opioid receptor antagonists

ABSTRACT

A compound of the formula (I) or a pharmaceutically acceptable salt, enantiomer, racemate, diasteromers or mixtures thereof, or a solvate thereof, formulations and methods of use thereof, as opioid receptor antagonists are disclosed wherein the variables are as described herein.

The present invention is in the field of medicinal chemistry. Theinvention relates specifically to compounds useful as opioidantagonists, methods of treatment, methods of using, and pharmaceuticalcompositions thereof.

BACKGROUND

Three types of opioid receptors, mu, kappa, and delta opioid receptorsare generally reported. Recent evidence points to the interactionsbetween receptor dimer combinations of mu, kappa and/or delta receptors(called heterodimers) as also contributing to opioid activity. Opioidreceptors and their normal regulation or lack thereof, has beenimplicated in disease states including irritable bowel syndrome, nausea,vomiting, pruritic dermatoses, depression, smoking and alcoholaddiction, sexual dysfunction, stroke and trauma in animals. Thereforeit is not surprising that the ability to antagonistically bind opioidreceptors has been shown to produce ameliorative, preventative and/ortreatment effects in animals including humans afflicted with one or moreof these disease states.

More recently, antagonists of the opioid receptors have been found toincrease metabolic energy consumption, and reduction of weight in obeserats while maintaining muscle mass. These findings indicate that aneffective opioid antagonist may be useful in preventing, treating and orameliorating the effect of obesity. Considering the percentage of thepopulation that is obese in Western societies and the indirect costsassociated with treating the effects and symptoms of obesity and RelatedDiseases, the impact of these findings cannot be overstated.

Though many opioid antagonists have been disclosed, the search continuesfor alternative and/or improved or more effective antagonists having anoverall benefit to the patient with little or no major side effects.U.S. Pat. No. 4,891,379 discloses phenylpiperidine opioid antagonistsuseful for the treatment of diabetes and obesity. Clinical developmentof a compound claimed in U.S. Pat. No. 4,191,771 was discontinued due topoor oral bioavailability characteristics. Bicyclic analogs of phenylpiperidine have been prepared and reported as opioid antagonists byWentland, et al., Biorganic and Medicinal Chemistry Letters 11 (2001)623-626; see also Wentland, et al., Biorganic and Medicinal ChemistryLetters 11 (2001) 1717-1721. Finally, European Patent application numberBP 1072592A2 filed May 18, 2000, discloses phenylpiperidine compounds offormula I

wherein A, D, R¹, R², R³, X, and n have meanings given in thedescription, which are useful in the prophylaxis and in the treatment ofdiseases mediated by opioid receptors such as pruritus.

In spite of these and other disclosures of compounds useful as opioidreceptor antagonists, there remains an unmet medical need for safe,effective and/or alternate treatment or prophylaxis of diseasesassociated with opioid receptors, particularly obesity and RelatedDiseases.

SUMMARY OF THE INVENTION

The present invention provides a compound of the formula (I)

or a pharmaceutically acceptable salt, solvate, enantiomer, racemate,diastereomer or a mixture thereof, wherein

X is C or N;

p is 0, 1, 2, or 3;n is 0, 1, or 2;R¹ and R² are independently selected from hydrogen, C₁₋₈alkyl,C₂-C₈alkenyl, C₂-C₈alkynyl, C₁-C₁₀alkylaryl, C₄-C₁₀-alkylcycloalkane,C₁-C₈alkoxyalkyl, (CH₂)_(n)C(O)OR⁸, (CH₂)_(n)C(O)R⁸, (CH₂)_(m)C(O)NR⁸R⁸,and (CH₂)_(m)NSO₂R⁸; wherein each of the alkyl, alkenyl, and aryl groupsare optionally substituted with one to five groups independentlyselected from C₁-C₈alkyl, C₂-C₈alkenyl, phenyl, C₁-C₈alkylaryl, andC₄-C₁₀alkylcycloalkane; and wherein R¹ and R² may optionally combinewith each other to form a 4, 5, 6, or 7-member nitrogen-containingheterocycle which nitrogen-containing heterocycle may further havesubstituents selected from the group consisting of oxo, amino, C₁₋₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, phenyl, C₁-C₈alkylaryl,C(O)C₁-C₈alkyl, CO(O)C₁-C₈alkyl, halo, C₁-C₈haloalkyl;R³ and R^(3′) are each independently selected from Hydrogen, C₁-C₈alkyl,C₂-C₈alkenyl, C₂-C₈alkynyl, phenyl, aryl, and C₁-C₈alkylaryl;R⁴, R⁵, and R⁶ are each independently selected from C₁-C₈alkyl,C₂-C₈alkenyl, C₂-C₈alkynyl, C₁-C₈alkoxy, halo, C₁-C₈haloalkyl, phenyl,aryl, C₁-C₈alkylaryl, (CH₂)_(m)NSO₂C₁-C₈alkyl, (CH₂)_(m)NSO₂phenyl,(CH₂)_(m)NSO₂aryl, —C(O)C₁-C₈alkyl, or —C(O)OC₁-C₈alkyl; wherein eachR⁴, R⁵, and R⁶ is attached to its respective ring only at carbon atoms,and wherein y is 0, 1, 2, or 3; and wherein z is 0, 1, 2, or 3R⁷ and R^(7′) are each independently selected from hydrogen, C₁-C₇alkyl,C₂-C₈alkenyl, C₂-C₈ alkynyl, C(O)C₁-C₈alkyl, hydroxy, C₁-C₈alkoxy,SO₂C₁-C₈alkyl, SO₂C₁-C₈alkylaryl, SO₂C₁-C₈alkylheterocyclic, aryl,C₁-C₈alkylaryl, C₃-C₇cycloalkane, C₁-C₁₀ alkylcycloalkane,(CH₂)_(n)C(O)OR⁸, (CH₂)_(n)C(O)R⁸, (CH₂)_(m)C(O)NR⁸R⁸, and(CH₂)_(m)NSO₂R⁸; wherein the alkyl, alkenyl, and aryl groups are eachoptionally substituted with one to five groups independently selectedfrom C₁-C₈alkyl, C₂-C₈alkenyl, phenyl, and C₁-C₈alkylaryl; and whereinR⁷ and R^(7′) may independently combine with each other, and with thenitrogen atom to which they are attached to form a 4, 5, 6, or 7-membernitrogen containing heterocycle which nitrogen containing heterocyclemay further have substituents selected from the group consisting of oxo,amino, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, phenyl, C₁-C₈alkylaryl,C(O)C₁-C₈alkyl, CO(O)C₁-C₈alkyl, hydroxy, C₁-C₈alkoxy, halo, andhaloalkyl;R⁸ is hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₅-C₈alkylaryl,(CH₂)_(m)NSO₂C₁-C₈alkyl, (CH₂)_(m)NSO₂Phenyl, (CH₂)_(m)NSO₂aryl,C(O)C₁-C₈alkyl, or —C(O)OC₁-C₈alkyl; and m is 1, 2.

The present invention also provides a method of using a compound offormula I for the prevention, treatment and/or amelioration of thesymptoms of obesity and Related Diseases comprising administering atherapeutically effective amount of a compound of formula I to a patientin need thereof.

The present invention also provides a pharmaceutical formulationcomprising a compound of formula I in association with a carrier,diluent and/or excipient.

The present invention relates to the use of a compound of formula I forthe treatment and/or prophylaxis of obesity and Related Diseasesincluding eating disorders (bulimia, anorexia nervosa, etc.), diabetes,diabetic complications, diabetic retinopathy, sexual/reproductivedisorders, depression, anxiety, epileptic seizure, hypertension,cerebral hemorrhage, congestive heart failure, sleeping disorders,atherosclerosis, rheumatoid arthritis, stroke, hyperlipidemia,hypertriglycemia, hyperglycemia, and hyperlipoproteinenamia, substanceabuse, drug overdose, compulsive behavior disorders (such as paw lickingin dog), addictive behaviors such as gambling.

The present invention provides a compound of formula (I) useful for themanufacture of a medicament for the treatment, prevention and/oramelioration of symptoms associated with obesity and Related Diseases.

In another embodiment, the present invention provides a compound offormula I or a pharmaceutically acceptable salt, solvate, enantiomer,racemate, diastereomer or a mixture thereof, useful as an appetitesuppressant.

DETAILED DESCRIPTION OR THE INVENTION

As used herein, the term “patient” includes human and non-human animalssuch as companion animals (dogs and cats and the like) and livestockanimals.

The preferred patient or subject of treatment, amelioration and/orprevention of obesity and Related Diseases is a human.

The terms “treating” and “treat”, as used herein, include theirgenerally accepted meanings, i.e., preventing, prohibiting, restraining,alleviating, ameliorating, slowing, stopping, or reversing theprogression or severity of a pathological condition, or sequela thereof,described herein.

The terms “ameliorating” “preventing”, “prevention of”, “prophylaxis”,“prophylactic” and “prevent” are used herein interchangeably and referto reducing the severity of the symptoms associated with obesity andRelated Diseases in a patient afflicted with same, or reducing thelikelihood that the recipient of a compound of formula I will incur ordevelop any of the pathological conditions, or sequela thereof,described herein.

As used herein, the term “effective amount” is synonymous with“effective dose” and means an amount of a compound of formula I that issufficient in one or more administrations for preventing, amelioratingor treating a condition, or detrimental effects thereof, hereindescribed, or an amount of a compound of formula I that is sufficientfor antagonizing the opioid receptors to achieve the objectives of theinvention.

The term “pharmaceutically acceptable” is used herein as an adjectiveand means substantially non-deleterious to the recipient patient.

The term “Active, Ingredient” as used herein means a compound of formulaI or a combination of compounds of formula I or a combination of acompound of formula I and a co-antagonist of the opioid receptor.

The term “formulation”, as in pharmaceutical formulation, or“pharmaceutical composition” is intended to encompass a productcomprising the Active Ingredient and the inert ingredient(s) that makeup the carrier, as well as any product which results, directly orindirectly, from combination, complexation or aggregation of any two ormore of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical formulations ofthe present invention encompass any effective composition made byadmixing a compound of the present invention and a pharmaceuticalcarrier. The pharmaceutical formulations of the present invention alsoencompass a compound of the formula I and a pharmaceutically acceptableco-antagonist of the opioid receptors useful for the treatment and/orprevention of obesity and/or Related Diseases.

The term “Related Diseases” as used herein refers to such symptoms,diseases or conditions caused by, exacerbated by, induced by or adjunctto the condition of being obese. Such diseases, conditions and/orsymptoms include but are not limited to eating disorders (bulimia,anorexia nervosa, etc.), diabetes, diabetic complications, diabeticretinopathy, sexual/reproductive disorders, depression (particularlythat induced by the awareness and loss of self esteem associated withobesity), anxiety, epileptic seizure, hypertension, cerebral hemorrhage,congestive heart failure, sleeping disorders, atherosclerosis,rheumatoid arthritis, stroke, hyperlipidemia, hypertriglycemia,hyperglycemia, and hyperlipoproteinenamia.

The term “suitable solvent” refers to any solvent or mixture ofsolvents, inert to the ongoing reaction that sufficiently solubilizesthe reactants to afford a medium within which the desired reaction isreasonably effected.

The term “mutual solvent” means a solvent that is used to dissolvesufficiently, two or more components of a reaction or mixture separatelyprior to reaction or mixing, that is a solvent common to more than onereagents or components of a mixture.

The term “nitrogen containing heterocycle” refers to a monocycle whichis a 4, 5, 6, or 7-member ring containing 1, 2 or 3 nitrogen atoms inaddition to the carbon atoms completing the ring size, or a combinationof 1 nitrogen atom and 1, or 2 atoms selected from oxygen, and sulfur inaddition to the appropriate number of carbon atoms completing the ringsize. A nitrogen containing heterocycle as used here may have 0, 1 or 3double bonds.

The term C₁-C₈alkyl refers to and includes all groups, structuralisomers and/or homologues of alkyl groups having from 1 to 8 carbonatoms. When the term C₁-C₈alkyl precedes or prefixes another group, theterm C₁-C₈alkyl, only limits the number of carbon atoms in the alkylcomponent. For example C₁-C₈alkyaryl means an aryl group having aC₁-C₈alkyl group substituent such that the number of carbon atoms in thegroup C₁-C₈alkylaryl is effectively the number of carbon atoms in thearyl group plus the number of carbon atoms in the C₁-C₈alkyl group.Similarly, the term C₁-C₈alkylcycloalkane, refers to a cycloalkane grouphaving a C₁-C₈alkyl substituent, and wherein the entire groupC₁-C₈alkylcycloalkane may itself be a substituent attached at either thealkyl group or the cycloalkyl group to a substrate.

The term “cycloalkane” means a cyclic alkyl group having from 3 to 8carbon atoms i.e. from cyclopropane to cyclooctane unless otherwiseindicated.

The term “halo” as used herein refers to a halogen including fluorine,chlorine, bromine or iodine.

As used herein the terms “alkenyl” refers to straight or branched carbonatoms having 1 or 2 carbon-carbon double bonds.

As used herein the terms “alkynyl” refers to straight or branched carbonatoms having 1 or 2 carbon-carbon triple bonds.

As used herein the term “alkoxy” refers to the group “O-alkyl” whereinalkyl is as indicated for the specific situation or as definedpreviously defined previously.

The term “aryl” as used herein refers to compounds or groups having theHuckel 4n+2 pi electron arrangement and includes phenyl, benzyl,naphthyl, but excludes carbazoles.

As used herein, the term “protecting group” refers to a group useful formasking reactive sites in a molecule to enhance the reactivity ofanother group or allow reaction at another desired site or sitesfollowing which the protecting group may be removed. Protecting groupsare usually used to protect or mask groups including but not limited to—H, —NH, and —COOH. Suitable protecting groups are known to one of skillin the art and are described in Protecting groups in Organic Synthesis,3^(rd) edition, Greene, T. W.; Wuts, P. G. M. Eds.; John Wiley and Sons,New York, 1999.

As used herein, the term “solvate” is a form of the compound of theinvention wherein a crystal or crystals of a compound of the inventionhave been formed from a stoichiometric or non-stoichiometric amount ofthe compound of formula I and a solvent Typical solvating solventsinclude for example, water, methanol, ethanol, acetone anddimethylformamide.

In those instances where a compound of the invention possesses acidic orbasic functional groups, various salts may be formed which are morewater soluble and/or more physiologically suitable than the parentcompound. Representative pharmaceutically acceptable salts include butare not limited to the alkali and alkaline earth salts such as lithium,sodium, potassium, calcium, magnesium, aluminum and the like. Salts areconveniently prepared from the free acid by treating the acid insolution with a base or by exposing the acid to an ion-exchange resin.

Included within the definition of pharmaceutically acceptable salts arethe relatively non-toxic, inorganic and organic base addition salts ofcompounds of the present invention, for example, ammonium, quaternaryammonium, and amine cations, derived from nitrogenous bases ofsufficient basicity to form salts with the compounds of this invention(see, for example, S. M. Berge, et al., “Pharmaceutical Salts,” J. Phar.Sci., 66:1-19 (1977)). Moreover, the basic group(s) of the compound ofthe invention may be reacted with suitable organic or inorganic acids toform salts such as acetate, benzenesulfonate, benzoate, bicarbonate,bisulfate, bitartrate, borate, hydrobromide, camsylate, carbonate,chloride, clavulanate, citrate, chloride, edetate, edisylate, estolate,esylate, fluoride, fumarate, gluceptate, gluconate, glutamate,glycolylarsanilate, hexylresorcinate, hydrochloride, hydroxynaphthoate,hydroiodide, isothionate, lactate, lactobionate, laurate, malate,malseate, mandelate, mesylate, methylbromide, methylnitrate,methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, palmitate,pantothenate, phosphate, polygalacturonate, salicylate, stearate,subacetate, succinate, tannate, tartrate, tosylate, trifluoroacetate,trifluoromethane sulfonate, and valerate.

A compound of the invention as illustrated by formula I may occur as anyone of its positional isomers, stereo chemical isomers or regioisomers,all of which are objects of the invention. Certain compounds of theinvention may possess one or more chiral centers, and thus, may exist inoptically active forms. Likewise, when the compounds contain an alkenylor alkenylene group, there exist the possibility of cis- andtrans-isomeric forms of the compounds. The R- and S-isomers and mixturesthereof, including racemic mixtures as well as mixtures of enantiomersor cis- and trans-isomers, are contemplated by this invention.Additional asymmetric carbon atoms can be present in a substituent groupsuch as an alkyl group. All such isomers as well as the mixtures thereofare intended to be included in the invention. If a particularstereoisomer is desired, it can be prepared by methods well known in theart by using stereospecific reactions with starting materials whichcontain the asymmetric centers and are already resolved or,alternatively by methods which lead to mixtures of the stereoisomers andsubsequent resolution by known methods. For example, a racemic mixturemay be reacted with a single enantiomer of some other compound i.e. achiral resolving agent. This changes the racemic form into a mixture ofstereoisomers and diastereomers, because they have different meltingpoints, different boiling points, and different solubilities and can beseparated by conventional means, such as, for example, crystallizationor chromatography.

The compound(s) of the present invention have shown inhibition oforexigenic effects, and are thus useful as appetite suppressants eitheras a single therapy or in conjunction with exercise and/or othereffective appetite suppressing or weight loss medications.

The efficacy of the compounds of the present invention has been shown bytheir activity in several biological activity models including an SPAGTP-gamma-S binding essay and other assays.

PREFERRED EMBODIMENTS OF THE INVENTION

A compound of formula I preferably exists as a pharmaceuticallyacceptable salt More preferred is the hydrochloride, or the bisulfatesalt, or the oxalic acid salt of the compound of formula I.

Though the groups R⁴, R⁵ and R⁶ may exist as multiple substituents ontheir respective ring substrates, a preferred embodiment of theinvention involves compounds wherein each of R⁴, R⁵, and R¹ are absent,or are singly or doubly substituted on their respective ring substrates.Preferred embodiments of the compound of formula I include thesubstructures Ia, Ib and Ic as shown below:

For the groups R¹ and R²

Preferred R¹ and R² groups are independently selected from the groupconsisting of Hydrogen, methyl, ethyl, propyl, pentyl, and isopropyl.Also preferred are R¹ and R² groups independently selected from thegroup consisting of:

each of which is optionally substituted with a group selected from thegroup consisting of halogen, C₁-C₈ alkyl, C₁-C₈ haloalkyl, C₁-C₈thioalkyl, C₁-C₈ alkylamino, phenyl; C₁-C₈ alkylsubstituted phenyl,C₄-C₈ heterocycle or C₁-C₄ alkyl heterocycle; or combine with a groupselected from C₁-C₈ alkyl, halogen, C₁-C₈ haloalkyl, C₁-C₈ thioalkyl,C₁-C₈ alkylamino, phenyl, C₁-C₈ alkylsubstituted phenyl, C₄-C₈heterocycle or C₁-C₄ alkyl heterocycle to form a substituted orunsubstituted bicycle.

Also preferred are R¹ and R² groups, which combine with each other andwith the nitrogen to atom to which they are attached to form a group,selected from the group consisting of

each of which is optionally substituted with a group selected from thegroup consisting of halogen, C₁-C₈ alkyl, C₁-C₈ haloalkyl, C₁-C₈thioalkyl, C₁-C₈ alkylamino, phenyl, C₁-C₈ alkylsubstituted phenyl,C₄-C₈ heterocycle or C₁-C₄ alkylheterocycle.

Preferred R³ and R^(3′) Groups

A preferred R³ is Hydrogen A preferred R^(3′) group is selected fromhydrogen, methyl, ethyl, propyl, isopropyl, phenyl and benzyl.

Preferred R⁴ Groups

A preferred R⁴ group is selected from the group consisting of halo,C₁-C₅ alkyl, C₁-C₅ haloalkyl, C₁-C₅ alkoxy, C₁-C₅ alkylamino, phenyl,C₁-C₅ alkylphenyl, C₁-C₅ alkylcycloalkyl, and C₁-C₅ thioalkyl. Morepreferred is a R⁴ group selected from the group consisting of methyl,ethyl, isopropyl, bromo, chloro, fluoro, trifluoromethyl, methoxy,ethoxy, thiomethyl, phenyl, and benzyl. A most preferred R⁴ group isselected from the group consisting of methyl, ethyl, isopropyl, fluoro,chloro, bromo, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy,and benzyl.

Preferred R⁵ Groups

A preferred R⁵ group is selected from the group consisting of halo,C₁-C₅ alkyl, C₁-C₅ haloalkyl, C₁-C₅ alkoxy, C₁-C₅ alkylamino, phenyl,C₁-C₅ alkylphenyl, C₁-C₅ alkylcycloalkyl, and C₁-C₅ thioalkyl. Morepreferred is an R⁵ group selected from the group consisting of methyl,ethyl, isopropyl, bromo, chloro, fluoro, trifluoromethyl, methoxy,ethoxy, thiomethyl, phenyl, and benzyl. A most preferred R⁵ group isselected from the group consisting of methyl, ethyl, isopopropyl,fluoro, bromo, chloro, trifluoromethyl, methoxy, ethoxy,

Preferred R⁶ Groups

A preferred R⁶ group is selected from the group consisting of halo,C₁-C₅ alkyl, C₁-C₅ haloalkyl, C₁-C₅ alkoxy, C₁-C₅ alkylamino, phenyl,C₁-C₅ alkylphenyl, C₁-C₅ alkylcycloalkyl, and C₁-C₅ thioalkyl. Morepreferred is an R⁶ group selected from the group consisting of methyl,ethyl, isopropyl, bromo, chloro, fluoro, trifluoromethyl; methoxy,ethoxy, thiomethyl, phenyl, and benzyl. A most preferred R⁶ group isselected from the group consisting of methyl, ethyl, isopopropyl,fluoro, bromo, chloro, trifluoromethyl, methoxy, ethoxy,trifluoromethoxy, and benzyl.

Though the groups R⁴, R⁵ and R⁶ may exist as multiple substituents ontheir respective ring substrates, a preferred embodiment of theinvention involves compounds wherein each of R⁴, R⁵ and R⁶ is absent, oris singly or doubly substituted on its respective ring substrate. In anyevent the requisite number of hydrogen atoms on the respective ring tosatisfy valency requirements is implied.

Preferred R⁷ and R^(7′) Groups

Preferred are R⁷ and R^(7′) groups independently selected from the groupconsisting of Hydrogen, methyl, ethyl, propyl, pentyl, isopropyl, phenyland benzyl,

Most preferred R⁷ and R^(7′) are hydrogen atoms.Preferred values for n and m, p, and z

A preferred value for n is 0, 1, or 2.

A preferred value for m is 1 or 2.

A preferred value for p is 0, 1, 2, or 3.

A preferred value for y or Z is 0, or 1 or 2.

Preferred A and C Rings

A preferred A ring is cyclopentane, or cyclohexane. A preferred C ringis phenyl, or pyridine

Preferred compounds of the invention include but are not limited tocompounds selected from the group consisting of

-   6-(8-Pentylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide,-   6-(5-Pentylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide,-   6-(5-Pentylamino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide,-   6-(1-Pentylamino-indan-5-yloxy)-nicotinamide,-   6-(1-Pentylamino-indan-4-yloxy)-nicotinamide,-   6-(8-Benzylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide,-   6-(5-Benzylamino-5,6,7,8-tetrahydronaphthalen-2-yloxy-nicotinamide,-   6-(5-Benzylamino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide,-   6-(1-Benzylamino-indan-4-yloxy)-nicotinamide,-   6-(8-Phenethylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide,-   6-(5-Phenethylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide,-   6-(5-Phenethylamino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide,-   6-(1-Phenethylamino-indan-4-yloxy)-nicotinamide,-   6-{8-[2-(3-Fluoro-phenyl)-ethylamino]-5,6,7,8-tetrahydro-naphthalen-2-yloxy}-nicotinamide,-   6-{5-[2-(3-Fluoro-phenyl)-ethylamino]-5,6,7,8-tetrahydro-naphthalen-2-yloxy}-nicotinamide,-   6-{5-[2-(3-Fluoro-phenyl)ethylamino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-nicotinamide,-   6-{3-[2-(3-Fluoro-phenyl)-ethylamino]-indan-5-yloxy}-nicotinamide,-   6-{1-[2-(3-Fluoro-phenyl)-ethylamino]-indan-5-yloxy}-nicotinamide,-   6-{1-[2-(3-Fluoro-phenyl)-ethylamino]-indan-4-yloxy}-nicotinamide,-   6-[8-(3-Methyl-butylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]nicotinamide,-   6-[5-(3-Methyl-butylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,-   6-[5-(3-Methyl-butylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-nicotinamide,-   6-[8-(4-Methyl-cyclohexylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,-   6-[5-(4-Methyl-cyclohexylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,-   6-[5-(4-Methyl-cyclohexylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-nicotinamide,-   6-[1-(4-Methyl-cyclohexylamino)-indan-5-yloxy]-nicotinamide,-   6-[1-(4-Methyl-cyclohexylamino)-indan-4-yloxy]-nicotinamide,-   6-(7-Pentylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide,-   6-(6-Pentylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide,-   6-(6-Pentylamino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide,-   6-(7-Pentylamino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide,-   6-(7-Benzylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide,-   6-(6-Benzylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide,-   6-(6-Benzylamino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide,-   6-(7-Benzylamino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide,-   6-(7-Phenethylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide,-   6-(6-Phenethylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy)nicotinamide,-   6-(6-Phenethylamino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide,-   6-(7-Phenethylamino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide,-   6-{7-[2-(3-Fluoro-phenyl)-ethylamino]-5,6,7,8-tetrahydro-naphthalen-2-yloxy}-nicotinamide,-   6-{6-[2-(3-Fluoro-phenyl)ethylamino]-5,6,7,8-tetrahydro-naphthalen-2-yloxy}-nicotinamide,-   6-{6-[2-(3-Fluoro-phenyl)-ethylamino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-nicotinamide,-   6-{7-[2-(3-Fluoro-phenyl)-ethylamino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-nicotinamide,-   6-[7-(3-Methyl-butylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,-   6-[6-(3-Methyl-butylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,-   6-[6-(3-Methyl-butylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-nicotinamide,-   6-[7-(3-Methyl-butylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-nicotinamide,-   6-[7-(4-Methyl-cyclohexylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,-   6-[6-(4-Methyl-cyclohexylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-nicotinamide,-   6-[7-(4-Methyl-cyclohexylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-nicotinamide,-   6-[7-(3-Phenyl-propylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,-   6-[6-(3-Phenyl-propylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,-   6-[6-(3-Phenyl-propylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-nicotinamide,-   6-[7-(3-Phenyl-propylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-nicotinamide,-   6-[5-(2-Methylsulfanyl-ethylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,-   6-[1-(2-Methylsulfanyl-ethylamino)-indan-5-yloxy]-nicotinamide,-   6-{5-[2-(3-Methoxy-phenyl)-ethylamino]-5,6,7,8-tetrahydro-naphthalen-2-yloxy}-nicotinamide,-   6-{1-[2-(3-Methoxy-phenyl)-ethylamino]-indan-5-yloxy}-nicotinamide,-   6-[5-(2-Dimethylamino-ethylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,-   6-[1-(2-Dimethylamino-ethylamino)-indan-5-yloxy]-nicotinamide,-   6-[5-(2-Pyrrolidin-1-yl-ethylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,-   6-[1-(2-Pyrrolidin-1-yl-ethylamino)-indan-5-yloxy]-nicotinamide,-   6-[5-(2-Pyridin-2-yl-ethylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,-   6-[1-(2-Pyridin-2-yl-ethylamino)-indan-5-yloxy]-nicotinamide,-   6-[5-(2-Morpholin-4-yl-ethylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,-   6-[1-(2-Morpholin-4-yl-ethylamino)-indan-5-yloxy]-nicotinamide,-   6-[1-(1,2-Diphenyl-ethylamino)-indan-5-yloxy]-nicotinamide,-   6-{5-[2-(4-Fluoro-phenyl)ethylamino]-5,6,7,8-tetrahydro-naphthalen-2-yloxy}-nicotinamide,-   6-{1-[2-(4-Fluoro-phenyl)-ethylamino]-indan-5-yloxy}-nicotinamide,-   6-[5-(2-Acetylamino-ethylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,-   6-[1-(2-Acetylamino-ethylamino)-indan-5-yloxy]-nicotinamide,-   6-{5-[2-(5-Fluoro-1H-indol-3-yl)-ethylamino]-5,6,7,8-tetrahydro-naphthalen-2-yloxy}-nicotinamide,-   6-{1-[2-(5-Fluoro-1H-indol-3-yl)-ethylamino]-indan-5-yloxy}-nicotinamide,-   3-[6-(5-Carbamoyl-pyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylamino]-propionic    acid isopropyl ester,-   3-[5-(5-Carbamoyl-pyridin-2-yloxy)-indan-1-ylamino]-propionic acid    isopropyl ester,-   6-(2-Pentylamino-indan-5-yloxy)-nicotinamide,-   6-(2-Pentylamino-indan-4-yloxy)-nicotinamide,-   6-(2-Benzylamino-indan-5-yloxy)-nicotinamide,-   6-(2-Benzylamino-indan-4-yloxy)-nicotinamide,-   6-[2-(3-Phenyl-propylamino)-indan-5-yloxy]-nicotinamide,-   6-[2-(3-Phenyl-propylamino)-indan-4-yloxy]-nicotinamide,-   6-[2-(3-Methyl-butylamino)-indan-5-yloxy]-nicotinamide,-   6-[2-(3-Methyl-butylamino)-indan-4-yloxy]-nicotinamide,-   6-[2-(2-Phenyl-propylamino)-indan-5-yloxy]-nicotinamide,-   6-[2-(2-Phenyl-propylamino)-indan-4-yloxy]-nicotinamide,-   6-(2-Phenethylamino-indan-5-yloxy)-nicotinamide,-   6-(2-Phenethylamino-indan-4-yloxy)-nicotinamide,-   6-{2-[(5-Fluoro-1H-indol-3-ylmethyl)-amino]-indan-5-yloxy}-nicotinamide,-   6-{2-[(5-Fluoro-1H-indol-3-ylmethyl)-amino]-indan-4-yloxy}-nicotinamide,-   6-[2-(3-Dimethylamino-2,2-dimethyl-propylamino)-indan-5-yloxy]-nicotinamide,-   6-[2-(3-Dimethylamino-2,2-dimethyl-propylamino)-indan-4-yloxy]-nicotinamide,-   6-{5-[(Benzo[b]thiophen-3-ylmethyl)-amino]-5,6,7,8-tetrahydro-naphthalen-2-yloxy}-nicotinamide,-   6-{1-[(Benzo[b]thiophen-3-ylethyl)-amino]-indan-5-yloxy}-nicotinamide,-   6-[5-(2-Methoxy-ethylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,-   6-[1-(2-Methoxy-ethylamino)-indan-5-yloxy]-nicotinamide,-   6-{5-[2-(3-Trifluoromethyl-phenyl)-ethylamino]-5,6,7,8-tetrahydro-naphthalen-2-yloxy}-nicotinamide,-   6-{1-[2-(3-Trifluoromethyl-phenyl)-ethylamino]-indan-5-yloxy}-nicotinamide,-   6-[5-(2-m-Tolyl-ethylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,-   6-{5-[2-(4-Fluoro-phenyl)-1,1-dimethyl-ethylamino]-5,6,7,8-tetrahydro-naphthalen-2-yloxy}-nicotinamide,-   6-{1-[2-(4-Fluoro-phenyl)-1,1-dimethyl-ethylamino]-indan-5-yloxy}-nicotinamide,-   6-[5-(3-Hydroxy-propylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,-   6-[1-(3-Hydroxy-propylamino)-indan-5-yloxy]-nicotinamide,-   6-[5-(2,2,2-Trifluoro-ethylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,-   6-[1-(2,2,2-Trifluoro-ethylamino)-indan-5-yloxy]-nicotinamide,-   6-[5-(2,2-Diphenyl-ethylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,-   6-[5-(4-Phenyl-piperidin-1-yl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,-   6-[1-(4-Phenyl-piperidin-1-yl)-indan-5-yloxy]-nicotinamide,-   6-[5-(Benzyl-methyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,-   6-[1-(Benzyl-methyl-amino)-indan-5-yloxy]-nicotinamide,-   6-[5-(3,4-Dihydro-1H-isoquinolin-2-yl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,-   6-[1-(3,4-Dihydro-1H-isoquinolin-2-yl)-indan-5-yloxy]-nicotinamide,-   6-(5-Thiomorpholin-4-yl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide,-   6-(1-Thiomorpholin-4-yl-indan-5-yloxy)-nicotinamide,-   2-[6-(5-Carbamoyl-pyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic    acid tert-butylamide,-   2-[6-(5-Carbamoyl-pyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic    acid tert-butylamide,-   6-[5-(5-Oxo-[1,4]diazepan-1-yl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,-   6-[1-(5-Oxo-[1,4]diazepan-1-yl)-indan-5-yloxy]-nicotinamide,-   6-[5-(Methyl-phenethyl-amino-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,-   6-[1-(3-Acetylamino-pyrrolidin-1-yl)-indan-5-yloxy]-nicotinamide,-   6-[1-(3-Phenyl-piperidin-1-yl)-indan-5-yloxy]-nicotinamide,-   6-[1-(3-Phenyl-pyrrolidin-1-yl)-indan-5-yloxy]-nicotinamide,-   6-[1-(3-Propylamino-propylamino)-indan-5-yloxy]-nicotinamide,-   6-[1-(3,3-Dimethyl-butylamino)-indan-5-yloxy]-nicotinamide,-   6-(1-Decylamino-indan-5-yloxy)-nicotinamide,-   6-[1-(2-Ethyl-hexylamino)-indan-5-yloxy]-nicotinamide,-   6-{1-[(Tetrahydro-furan-2-ylmethyl)-amino]-indan-5-yloxy}-nicotinamide,-   6-(1-Cycloheptylamino-indan-5-yloxy)nicotinamide,-   6-{1-[2-(1-Methyl-pyrrolidin-2-yl)-ethylamino]-indan-5-yloxy}-nicotinamide,-   6-(1-Cyclopropylamino-indan-5-yloxy)-nicotinamide,-   6-[1-(1,3-Dimethyl-butylamino)-indan-5-yloxy]-nicotinamide,-   6-(1-Cyclooctylamino-indan-5-yloxy)-nicotinamide,-   6-[1-(2,3-Dimethyl-cyclohexylamino)-indan-5-yloxy]-nicotinamide,-   6-(1-Cyclobutylamino-indan-5-yloxy)-nicotinamide,-   6-(1-Cyclopentylamino-indan-5-yloxy)-nicotinamide,-   6-[1-(Cyclohexylmethyl-amino)-indan-5-yloxy]-nicotinamide,-   6-{1-[(1-Ethyl-pyrrolidin-2-ylmethyl)-amino]-indan-5-yloxy}-nicotinamide,-   6-[1-(3-Cyclohexylamino-propylamino)-indan-5-yloxy]-nicotinamide,-   6-[1-(3-Methyl-cyclohexylamino)-indan-5-yloxy]-nicotinamide,-   6-(1-Cyclohexylamino-indan-5-yloxy)-nicotinamide,-   6-[1-(1-Isopropyl-2-methyl-propylamino)-indan-5-yloxy]-nicotinamide,-   6-[1-(2-Cyclohex-1-enyl-ethylamino)-indan-5-yloxy]-nicotinamide,-   6-[1-(2-Methyl-butylamino)-indan-5-yloxy]-nicotinamide,-   6-[1-(4-Hydroxy-cyclohexylamino)-indan-5-yloxy]-nicotinamide,-   6-[1-(1,4-Dimethyl-pentylamino)-indan-5-yloxy]-nicotinamide,-   6-[1-(1-Cyclohexyl-ethylamino)-indan-5-yloxy]-nicotinamide,-   6-[1-(3,3,5-Trimethyl-cyclohexylamino)-indan-5-yloxy]-nicotinamide,-   6-[1-(2-Carbamoyl-cyclohexylamino)-indan-5-yloxy]-nicotinamide,-   6-[1-(Cyclopropylmethyl-amino)-indan-5-yloxy]-nicotinamide,-   6-[1-(3-Butoxy-propylamino)-indan-5-yloxy]-nicotinamide,-   6-[1-(2,2,3,3,4,4,4-Heptafluoro-butylamino)-indan-5-yloxy]-nicotinamide,-   6-{1-[3-(2-Oxo-pyrrolidin-1-yl)-propylamino]-indan-5-yloxy}-nicotinamide,-   6-[1-(3-Azepan-1-yl-propylamino)-indan-5-yloxy]-nicotinamide,-   6-[1-(2,2,3,3,3-Pentafluoro-propylamino)-indan-5-yloxy]-nicotinamide,-   6-{1-[(2-Hydroxy-cyclooctylmethyl)-amino]-indan-5-yloxy}-nicotinamide,-   6-[1-(Bicyclohexyl-2-ylamino)-indan-5-yloxy]-nicotinamide,-   6-[1-(2-Hydroxy-cyclohexylamino)-indan-5-yloxy]-nicotinamide,-   6-{1-[2-(2-Methyl-cyclohexyl)-ethylamino]-indan-5-yloxy}-nicotinamide;-   6-{1-[2-(4-Methyl-cyclohexyl)-ethylamino]-indan-5-yloxy}-nicotinamide,-   6-[1]-(2-Cyclopentyl-ethylamino)-indan-5-yloxy)-nicotinamide,-   6-[1-(Phenethylamino-methyl)-indan-5-yloxy]-nicotinamide,-   6-[8-Phenethylamino-methyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,-   6-[3-(Phenethylamino-methyl)-indan-5-yloxy]-nicotinamide,-   6-[5-(Phenethylamino-methyl)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-nicotinamide,-   6-[1-(Benzylamino-methyl)-indan-5-yloxy]-nicotinamide,-   6-[8-(Benzylamino-methyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,-   6-[3-(Benzylamino-methyl)-indan-5-yloxy]-nicotinamide,-   6-[5-(Benzylamino-methyl)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-nicotinamide,-   6-{1-[(3-Methyl-butylamino)-methyl]-indan-5-yloxy}-nicotinamide,-   6-{8-[(3-Methyl-butylamino)-methyl]-5,6,7,8-tetrahydro-naphthalen-2-yloxy}-nicotinamide,-   6-{3-[(3-Methyl-butylamino)-methyl]-indan-5-yloxy}-nicotinamide,-   6-{5-[(3-Methyl-butylamino)-methyl]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-nicotinamide,-   6-{1-[(2-Cyclohexyl-ethylamino)-methyl]-indan-5-yloxy}-nicotinamide,-   6-{8-[(2-Cyclohexyl-ethylamino)-methyl]5,6,7,8-tetrahydro-naphthalen-2-yloxy}-nicotinamide,-   6-{5-[(2-Cyclohexyl-ethylamino)-methyl]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-nicotinamide,-   6-{1-[(Cyclohexylmethyl-amino)-methyl]-indan-5-yloxy}-nicotinamide,-   6-{8-[(Cyclohexylmethyl-amino)-methyl]-5,6,7,8-tetrahydro-naphthalen-2-yloxy}-nicotinamide,-   6-{3-[(Cyclohexylmethyl-amino)-methyl]-indan-5-yloxy}-nicotinamide,-   6-{5-[(Cyclohexylmethyl-amino)-methyl]-5,6,7,9-tetrahydro-naphthalen-1-yloxy}-nicotinamide,-   6-{1-[(2-Cyclopentyl-ethylamino)-methyl]-indan-5-yloxy}-nicotinamide,    and a pharmaceutically acceptable salt, solvate or enantiomer    thereof.

Most preferred compounds of the invention include compounds selectedfrom the group consisting of:

-   6-(6-Pentylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide,-   6-(5-Pentylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide,-   6-(5-Pentylamino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide,-   6-(1-Pentylamino-indan-5-yloxy)-nicotinamide,-   6-(1-Pentylamino-indan-4-yloxy)-nicotinamide,-   6-(8-Benzylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide,-   6-(5-Benzylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide,-   6-(5-Benzylamino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide,-   6-(1-Benzylamino-indan-4-yloxy)-nicotinamide,-   6-(8-Phenethylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide,-   6-(5-Phenethylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide,-   6-(5-Phenethylamino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide,-   6-(1-Phenethylamino-indan-4-yloxy)-nicotinamide,-   6-{8-[2-(3-Fluoro    phenyl)-ethylamino]-5,6,7,8-tetrahydro-naphthalen-2-yloxy}-nicotinamide,    and a pharmaceutically acceptable salt, solvate or enantiomer    thereof.

Preparing the Compound of the Invention

Compounds of formula I may be prepared as described in the followingSchemes and Examples. The compounds employed as initial startingmaterials in the synthesis of compounds of the invention are well knownand, to the extent not commercially available, are readily synthesizedusing specific references provided, or by standard procedures commonlyemployed by those of ordinary skill in the art and/or are found ingeneral reference texts.

More particularly, the compounds of the invention are produced inaccordance with schemes 1 through 10 that are described in detail below,or analogous methods thereto. These reactions are often carried outfollowing known procedures, methods, or analogous methods thereto.Examples of such known procedures and methods include those described ingeneral reference texts such as Comprehensive Organic Transformations,VCH Publishers Inc, 1989; Compendium of Organic Synthetic Methods,Volumes 1-10, 1974-2002, Wiley Interscience; Advanced Organic Chemistry,Reactions Mechanisms, and Structure, 5^(th) Edition, Michael B. Smithand Jerry March, Wiley Interscience, 2001; Advanced Organic Chemistry,4^(th) Edition, Part B) Reactions and Synthesis, Francis A. Carey andRichard J. Sundberg, Kluwer Academic/Plenum Publishers, 2000, etc., andreferences cited therein.

Compounds of the present invention are generally prepared starting witha coupling reaction to form the ether linkage between the aryl groupsAr² and Ar³. The alkylamino appendage or substituent on the bicyclicring Ar² is formed by reductive animation on a keto functionalityalready present on the ring followed by elaboration of the substituentto form the desired group. The final compound is then obtained byelaboration of a cyano or amido group on the ring Ar³. Alternatively theside chain on Ar² is formed by displacement of an alkylhalidesubstituent on the Ar² ring. The alkylhalide substituent is itselfintroduced via a hydroxy group or a reduced keto group. Details ofspecific procedures are provided in the schemes below.

As shown in scheme 1, certain compounds of the present invention areprepared starting with an optionally substituted hydroxytetralonecompound 1. The tetralone compound provides the framework for the6,6-bicyclic structure representing Ar² of formula I. Thehydroxytetralone 1 is typically reacted with a halonicotinonitrilecompound or a halonicotinamide 2 to afford the ether linked compound 3.Various positional isomers of hydroxytetralone, halonicotinonitrile orhalonicotinamide may be employed to effect preparation of positionisomers or analogs of the compound 3. Preferred halogen substituents forthe displacement reaction are fluoro, chloro, or bromo. The displacementreaction is preferably performed under basic conditions such as withsodium or potassium carbonate in a suitable polar solvent such as forexample, dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the like. The reaction is typically performed atemperatures ranging from room temperature to reflux temperaturesdepending on the particular substrates. The ether 3 is then reductivelyaminated with a suitable amine to form the compound 4 or 5. The use of aprimary amine results in the amine 4, which may be further converted tothe tertiary amine 5 using processes known to one of skill in the artand/or disclosed in the experimental section. Alternatively, where atertiary amine is desired and the reaction is not likely to bedetrimentally affected by steric considerations, a secondary amine maybe used in the reductive amination step to afford the compound 5 oranalog thereof.

Preparing the benzamide analog of the compounds of formula 4 or 5 may beaccomplished by using the appropriately substituted benzamide orbenzonitrile as shown in scheme 2 below.

For Schemes 1 and 2, wherein the C-ring of formula I is introduced viathe nitrile, the resulting nitrile may be converted to the amide bybasic hydrolysis in the presence of hydrogen peroxide. Details of thisand other methods of hydrolyzing nitrile to amide are known to one ofskill in the art and/or are disclosed in the experimental section. Wherethe nitrile is used in the initial reaction, it may be preferable forsome substrates that the conversion to the amide be effected prior tothe reductive amination step. As in Scheme 1,

The indane analog (wherein the A-ring is a 5-member ring) of compoundsof formula I may be similarly prepared using the desired 2-hydroxyindanone as starting material in a scheme such as Scheme 2 above. Aswith Scheme 1, the coupled product 7 is then reductively aminated withammonia or a desired substituted amine to afford the compound 8 or 9directly.

Compounds of formula I wherein the appropriately substitutedhydroxytetralone or hydroxyindanone or hydroxy tetrahydroisoquinoline isnot commercially available may be accessed starting from thecorresponding methoxy compound 10 as shown in Scheme 3.

Protection of the hydroxy group as the methoxy group as in compound 10also allows for installation of the amino side chain on the bicyclicring via a displacement reaction of an intermediate halide. As shown inScheme 3, the tetralone or indanone compound 10 is reduced to thealcohol 11 using known reducing agents such as the borohydride reagentse.g. sodium borohydride, or the aluminum hydride reducing agents, e.g.NaAlH₄. The procedures and conditions for effecting such reductions areknown to one of skill in the art, may be found in general organicreference texts disclosed herein or are disclosed in the experimentalsection. The alcohol 11 is then displaced with a nucleophile source toafford a leaving group such as for example, chloride or bromide or othersulfonate ester. Formation of chloride leaving group for example, isaccomplished by reacting the intermediate 11 with for example, thionylchloride in a suitable solvent such as toluene or dichloromethane attemperatures ranging from ambient to reflux temperatures. The resultingchloride 12 is displaced with an amine in a suitable polar aproticsolvent to afford either the primary, secondary or tertiary aminedepending on whether the reacting amine source is ammonia, primary orsecondary amine. The reactive hydrogen of a primary or secondary amine13 (where one or both of R¹ and R² are hydrogen) may be protected as theBoc-group after de-methylation to form compound 15. Compound 15 may bereacted with a source of nicotinamide or nicotinonitrile or benzamide orbenzonitrile as desired. The use of optionally substituted3-halonicotinamide is shown in the Scheme 3. One of skill in the art isaware that other sources of the Ar3 group according to formula I may beintroduced as discussed herein or as disclosed in the experimentalsection.

A modification of the scheme 3 protocol wherein the coupling to form theether backbone of a compound of formula I is effected prior to formationof the amino side chain is shown in scheme 4 below.

According to Scheme 4, the starting material 10 is de-methylated toafford the hydroxy compound 18. The de-methylation may be accomplishedby use of 48% HBr or boron tribromide. Details of the procedures foreffecting the above de-methylation has been discussed previously, areknown to one of skill in the art and/or disclosed in the experimentalsection herein. The hydroxy compound 18 is then coupled with a benzamideor nicotinonitrile or other source of the C-ring of a compound offormula L The use of halonicotinonitrile in shown in the scheme above toafford the ether compound 19. The conditions to effect the couplingreaction have been described earlier and in the experimental section.The ether 19 is reductively aminated at the carbonyl group to afford theamine compound 17. The amine 17 may be converted to the compound 20wherein both R¹ and R² are not hydrogen atoms following procedures knownto one of skill in the art.

Compounds of formula I wherein the alkyl chain length of the amino sidechain i.e. p is 1, may be prepared following the protocol of Scheme 5below or known variations thereof.

As shown in Scheme 5, 5-methoxy indanone (21) may be reacted withdimethylcarbonate in the presence of a strong base such as sodiumhydride to afford the 5-methoxy-indan-1-oxo-2-carboxylic acid methylester (22). The indanone ester 22 may be reduced to the indane methylester 23 using palladium on carbon in the presence of a proton donorsuch as perchloric acid, and a suitable solvent such as acetic acid. Theresulting indane methylester 23 is further reduced to the methoxyindanealcohol 24 using lithium aluminum hydride or other suitable reducingagents. The free hydroxy group of compound 24 may be protected usingsuitable OH-protecting groups prior to de-methylation reaction of 24 toafford the product 25. The removal of the methoxy group of the protectedmethoxyindane alcohol 24 may be accomplished using concentrated HBr,e.g. 48% HBr. Alternatively, boron tribromide may be used. The resultinghydroxy compound 25 is then coupled with a source of nicotinonitrile,nicotinamide, benzonitrile or benzamide. A suitable source in each caseis an appropriately substituted halide. Scheme 5, for example shows theuse of a halonicotinamide. A preferred halogen is the chloride. Thecoupling reaction to form the ether linkage has been describedpreviously, and affords the ether 26 following deprotection asappropriate. Oxidation of the alcoholic functionality of the ether 26affords the aldehyde 27. Specific procedures for oxidation of thealcohol include the Swern oxidation. The Swern oxidation may beaccomplished by adding the alcohol 26 into a cold solution/mixtureformed by adding dimethyl sulfoxide to a solution of oxalyl chloride ina suitable solvent such as dichloromethane. Detailed procedures foreffecting the Swern oxidation and other methods of oxidizing alcoholsare provided in general reference texts, are known to one of skill inthe art, and/or disclosed in the experimental section herein. Thealdehyde 27 is then reductively aminated with the desired amine toafford the compound 28.

Compounds of formula I wherein p is 2 may be prepared by the proceduregiven in schemes 7 or 8 below or analogous procedures obtained bymodifications known to one of skill in the art.

Compound 29 of Scheme 6 may be converted to compound 30 via a series ofreactions beginning with formation of an acrylonitrile via theHorner-Emmons-Wadsworth modification of the Wittig reaction usingdiethylphosphonoacetonitrile diethylcyanomethyl phosphonate to form anacrylonitrile intermediate (see J. Org. Chem 30, 505 (1965) and also J.Am. Chem. Soc., 83 1733 (1961). The acrylonitrile intermediate orsubstituted derivative thereof, may be reduced to the saturated nitrile30 using for example hydrogenation using palladium (II) chloridecatalyst, and sodium borohydride in a protic solvent such as methanol.For reference see Jelliman, C., et al., J. Med. Chem., 43 (22) 4051-4062(2000). The nitrile 30 may be reduced to the ethylamine derivative 31 byhydrogenation using Raney Nickel and ammonium hydroxide in THF asdisclosed in Jelliman et al., supra. The ethylamine compound 31 may bedemethylated to form the hydroxy compound 32. The hydroxy compound 32may be reacted directly with a nicotinamide source or a benzamide sourceor synthon to afford a compound of the invention. Alternatively thehydroxy compound 32 is protected at the amine prior to coupling with anicotinamide or benzamide source or synthon. The protected compound 33is coupled with a source of the “C” ring to afford the coupled andprotected compound 34. The compound 34 is then de-protected to affordthe desired compound of the invention 35 which may itself be convertedto other substituted amine derivatives such as compound 36 followingprocedures known to one of skill in the art or disclosed herein. One ofskill in the art is aware that compounds of formula I wherein R³ and/orR^(3′) are other than hydrogen may be prepared by alkylation at the freemethyne carbon atom of the acrylonitrile intermediate from compound 29,or the nitrile 30 to afford substituted derivatives of a compound offormula I. Such alkylations may be accomplished by following proceduressimilar to those disclosed in Synthesis, 516 (19750.

In an alternate method, compounds of formula I wherein p is 2 may beprepared following a scheme such as Scheme 7.

As shown in Scheme 7, methoxy tetralone 37 is subjected to a Knoevenageltype nucleophilic substitution with ethylcyanoacetate to afford uponelimination of water, the acrylonitrile acetate compound 38 according toprocedures described in Mukhopadhyay et al. J. Chem Res, Synop 1993, 12,47&477. Other examples of the Knoevenagel reaction may be found in NameReactions and Reagents in Organic Synthesis by Bradford P. Mundy andMichael G, Ellerd, Wiley InterScience Publishers, 1988, New York, NewYork and references cited therein. The compound 38 is then subjected toa decarboxylation and reduction sequence to afford the aminoethylcompound 40 according to a procedure similar to that described in New etal., Synthesis 1983, 388. The resulting 4-methoxy aminoethyl compound 40is then demethylated to afford the hydroxy compound 41 using, forexample, boron tribromide or 48% HBr as the demethylating agent. Thehydroxy compound 41 is then reacted with an appropriately substitutedhalo nicotinamide or halo-benzamide source (e.g. 4-chlorobenzenecarboxamide shown) or synthon thereof, to afford the ether compound 42.The ether compound 42 may be elaborated to substituted amines byprocedures known to one of skill in the art.

In yet an alternative procedure compounds of formula I wherein p is 2may be prepared following a scheme such as Scheme 8.

According to Scheme 8, compound 28 (Scheme 5) may be hydrolyzed to theacid 29. The acid 29 is further converted to an acid halideintermediate, e.g. acyl chloride, using for example, thionyl chloride inan aprotic solvent. The acyl halide intermediate is then converted to adiazoketone intermediate by reaction with diazomethane. The diazoketoneintermediate is converted to a methylester intermediate which upon aArndt-Eistert reaction affords the acid 43. Procedures for convertingthe acid 29 to the acid 43 are similar to those employed and disclosedin Walsh, E. J., et al, Tetrahedron Letters, 1986, (27) 1127-1130 andreferences therein. The acid 43 is then reduced to the alcohol using,for example, lithium aluminum-hydride. The intermediate alcohol isconverted to a chloride intermediate by reaction with thionyl chlorideor other chlorinating agent. The chloride intermediate is displaced withammonia or amine to afford the primary or substituted amine 44respectively. The methoxy amine compound 44 is then de-methylated at themethoxy group to form the alcohol 45. The alcohol 45 is then coupledwith an appropriately substituted halonicotinamide, halo-benzamide orother desired heterocyclic amide source or synthon to afford compound46, a compound of the invention.

Compounds of formula I wherein p for the amine side chain is 3 may beprepared as shown in scheme 9.

As shown in scheme 9, compound 22 which formation has been discussedpreviously, may be converted to the acid 23 by basic hydrolysis followedby acidic workup. The acid 23 may be reduced to the aldehyde 47.Procedures for reduction of acids to aldehydes are known to one of skillin the art. The aldehyde 47 is then reacted with malonic acid in thepresence of a base to afford the acrylic acid 48. The acrylic acid 48 isreduced in one or two steps to the propanol derivative 49. The propanolderivative 49 is then converted to the primary amine or the substitutedamine depending on whether ammonia or a substituted amine is used toreact with the propyl chloride derivative 50 formed from a halogenationreaction of the propanol derivative 49. The halogenation of the propanolderivative 49 is effected with thionyl chloride or other chlorinatingagent. The chloride 50 is then displaced with an amine source to affordthe desired amine component 51. The methoxy group of the amine 51 may bereduced to the hydroxy group using procedures described herein to affordthe phenoxy compound 52. The phenoxy compound 52 may be coupled with asource of nicotinamide, benzamide, synthon thereof, or other source ofthe C-ring of compound of formula I to afford the compound 53, acompound of the invention.

Method of Using the Invention

As noted above, the compounds of the present invention are useful inblocking the effect of agonists at mu, kappa, and/or delta opioidreceptors. As such, the present invention also provides a method forblocking a mu, kappa, delta receptor or receptor combinationheterodimer) thereof in mammals comprising administering to a mammalrequiring blocking of a mu, kappa, delta or combinations of mu, kappa,and/or delta receptors, a receptor blocking dose of a compound offormula I.

The term “receptor blocking dose”, as used herein, means an amount of acompound of formula I necessary to block a mu, kappa, or delta receptoror receptor combination (heterodimer) thereof following administrationto a mammal requiring blocking of a mu, kappa, or delta receptor orreceptor combination (heterodimer) thereof.

The compounds of formula I or combinations thereof, are effective over awide dosage range. For example, dosages per day will normally fallwithin the range of about 0.05 to about 250 mg/kg of body weight. In thetreatment of adult humans, the range of about 0.05 to about 10 mg/kg, insingle or divided doses, is preferred. However, it will be understoodthat the amount of the compound actually administered will be determinedby a physician in light of the relevant circumstances, including thecondition to be treated, the choice of compound to be administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the chosen route of administration, andtherefore the above dosage ranges are not intended to limit the scope ofthe invention in any way. The compounds may be administered by a varietyof routes such as the oral, transdermal, subcutaneous, intranasal,intramuscular and intravenous routes.

A variety of physiologic functions have been shown to be subject to orinfluenced by mu, kappa, or delta receptors or receptor combination(heterodimers) in the brain. As such, the compounds of the presentinvention are believed to have the ability to treat a variety ofdisorders in mammals associated with these receptors or combinationsthereof, such as eating disorders, opioid overdose, depression, smoking,alcoholism, sexual dysfunction, shock, stroke, spinal damage and headtrauma As such, the present invention also provides methods of treatingthe above disorders by blocking the effect of agonists at a mu, kappa,delta receptor or receptor combination heterodimer) thereof. Thecompounds of the present invention have been found to display excellentactivity in an opioid receptor binding assay which measures the abilityof the compounds to block the mu, kappa, delta or receptor combination(heterodimer) thereof.

GTP-γ-S Binding Assay

A scintillation proximity assay (SPA) based GTP-γ-S³⁵ assay format wasdeveloped based on previous opioid (Emmerson et al., J. Pharm Exp Ther278, 1121, 1996; Horng et al., Society for Neuroscience Abstracts,434.6, 2000) and muscarinic (DeLapp et al., JPET 289, 946, 1999) assayformats. Membranes were resuspended in 20 mM HEPES, 100 mM NaCl, 5 mMMgCl₂, 1 mM DTT, and 1 mM EDTA. Fifty mL of GTP-γ-[35S], compound,membrane suspension (20 microgram/well), and wheat germ agglutinincoated SPA beads (1 mg/well) were added to clear bottom 96 well assayplates. GDP (200 mM) was added to the membrane solution prior toaddition to the assay plates. Plates were sealed and incubated for fourhours at room temperature then placed in a refrigerator overnight toallow the beads to settle. Signal stability at 4° C. was determined tobe >60 hours. Plates were warmed to room temperature and counted in aWallac Microbeta scintillation counter. For antagonist assays, specificagonists were added at the following concentrations: (MOR) DAMGO 1micromolar, (DOR) DPDPE 30 nM, (KOR) U69593 300 nM. Kb's were determinedby Cheng-Prusoff equation (see Cheng and Prusoff, Biochem. Pharmacol.22, 3099, 1973). Results obtained for a sample of compounds of theinvention in the GTP-γ-S Binding Assay are shown in table 1 below.

TABLE 1 Compound of Mu Kb Kappa Kb Delta Kb Example IUPAC name (nM) (nM)(nM) 90 6-{1-[2-(4-Fluoro- 0.4 9.2 14.6 phenyl)- ethylamino]-indan-5-yloxy}- nicotinamide 195 6-{5-[(2- 0.5 76.0 7.9 Cyclohexyl-ethylamino)- methyl]-5,6,7,8- tetrahydro- naphthalen-1-yloxy}-nicotinamide 192 6-{5-[(3-Methyl- 1.1 11.8 9.4 butylamino)-methyl]-5,6,7,8- tetrahydro- naphthalen-1- yloxy}-nicotinamide 2026-{5-[(3,3-Dimethyl- 0.65 5.79 4.09 butylamino)- methyl]-5,6,7,8-tetrahydro- naphthalen-1- yloxy}-nicotinamide 20 6-{1-[Methyl-(3- 0.732.5 13.48 methyl-butyl)- amino]-indan-5- yloxy}-nicotinamide

Formulation

While it is possible to administer a compound of the invention directlywithout any formulation, the compounds are preferably employed in theform of a pharmaceutical formulation comprising a pharmaceuticallyacceptable carrier, diluent or excipient and a compound of theinvention. Such compositions will contain from about 0.1 percent byweight to about 90.0 percent by weight of a present compound. As such,the present invention also provides pharmaceutical formulationscomprising a compound of the invention and a pharmaceutically acceptablecarrier, diluent or excipient thereof.

In making the compositions of the present invention, the activeingredient will usually be mixed with a carrier, or diluted by acarrier, or enclosed within a carrier which may be in the form of acapsule, sachet, paper or other container. When the carrier serves as adiluent, it may be a solid, semi-solid or liquid material that acts as avehicle, excipient or medium for the active ingredient. Thus, thecomposition can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, emulsions, solutions, syrups, suspensions,aerosols (as a solid or in a liquid medium, and soft and hard gelatincapsules.

Examples of suitable carriers, excipients, and diluents include lactose,dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calciumphosphate, alginates, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, tragacanth, gelatin, syrup, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate,water, and mineral oil. The formulations may also include wettingagents, emulsifying and suspending agents, preserving agents, sweeteningagents or flavoring agents. The formulations of the invention may beformulated so as to provide quick, sustained, or delayed release of theactive ingredient after administration to the patient by employingprocedures well known in the art.

For oral administration, a compound of this invention ideally can beadmixed with carriers and diluents and molded into tablets or enclosedin gelatin capsules.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 1 to about 500 mg, more usually about 5 toabout 300 mg, of the active ingredient. The term “unit dosage form”refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalcarrier.

In order to more fully illustrate the operation of this invention, thefollowing formulation examples are provided. The examples areillustrative only, and are not intended to limit the scope of theinvention. The formulations may employ as active compounds any of thecompounds of the present invention.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

Amount Concentration by weight Compound per capsule (mg) (%)Cyclohexyl-3-hydroxy- 250 55 propyl)-3,4-dimethyl-piperidin-4-yl]-benzamide Starch dried 200 43 Magnesium stearate 10 2

The above ingredients are mixed and filled into hard gelatin capsules in460 mg quantities.

Formulation 2

Capsules each containing 20 mg of medicament are made as follows:

Amount Concentration by weight Compound per capsule (mg) (%)Cyclohexyl-3-hydroxy- 20 10 propyl)-3,4-dimethyl-piperidin-4-yl]-benzamide Starch 89 44.5 Microcrystalline 89 44.5cellulose Magnesium stearate 2 1

The active ingredient, cellulose, starch and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve and filled into a hardgelatin capsule.

Formulation 3

Capsules each containing 100 mg of active ingredient are made asfollows:

Amount Concentration by weight Compound per capsule (mg) (%)Cyclohexyl-3-hydroxy- 100 30 propyl)-3,4-dimethyl-piperidin-4-yl]-benzamide Polyoxyethylene 50 mcg 0.02 Sorbitanmonooleate Starch powder 250 69.98

The above ingredients are thoroughly mixed and placed in an emptygelatin capsule.

Formulation 4

Tablets each containing 10 mg of active ingredient are prepared asfollows:

Amount Concentration by weight Compound per capsule (mg) (%)Cyclohexyl-3-hydroxy- 10 10 propyl)-3,4-dimethyl-piperidin-4-yl]-benzamide Starch 45 45 Microcrystalline 35 35 cellulosePolyvinylpyrrolidone 4 4 (as 10% solution in water) Sodium carboxymethyl4.5 4.5 starch Magnesium stearate 0.5 0.5 talc 1 1

The active ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granule so produced isdried at 50-60° C. and passed through a No. 18 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate and laic, previouslypassed through a No. 60 mesh U.S. sieve, are then added to the granulewhich, after mixing, is compressed on a tablet machine to yield a tabletweighing 100 mg.

Formulation 5

A tablet formula may be prepared using the ingredients below:

Percent by weight Compound Amount per capsule (mg) (%)Cyclohexyl-3-hydroxy- 250 38 propyl)-3,4-dimethyl-piperidin-4-yl]-benzamide Cellulose 400 60 microcrystalline Silicondioxide fumed 10 1.5 Stearic acid 5 0.5

The components are blended and compressed to form tablets each weighing665 mg.

Formulation 6

Suspensions each containing 5 mg of medicament per 5 ml dose are made asfollows:

Amount per 5 mL Compound suspension (ml) Cyclohexyl-3-hydroxy- 5propyl)-3,4-dimethyl- piperidin-4-yl]-benzamide Sodium carboxymethyl 50cellulose Syrup 1.25 Benzoic acid solution 0.10 Flavor q.v. Color q.v.Water q.s. to 5 mL

The medicament is passed through a No. 45 mesh U.S. sieve and mixed withthe sodium carboxymethylcellulose and syrup to form a smooth paste. Thebenzoic acid solution, flavor and color is diluted with some of thewater and added to the paste with stirring. Sufficient water is thenadded to produce the required volume.

Formulation 7

An aerosol solution is prepared containing the following components:

Concentration by weight Compound (percent)Cyclohexyl-3-hydroxy-propyl)-3,4- 0.25dimethyl-piperidin-4-yl]-benzamide hydrochloride Ethanol 29.75Propellant 22 70.0 (chlorodifluoromethane)

The active compound is mixed with ethanol and the mixture added to aportion of the Propellant 22, cooled to −30° C. and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted further with the remaining amount of propellant.The valve units are then fitted to the container.

EXPERIMENTAL SECTION Intermediate 15-(8-Oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide

Combine 7-hydroxy-1-tetralone (J. Med. Chem. (1998), 41(7), 1068-1083),(3.37 g, 20.7 mmol), 6-chloronicotinamide (available from AldrichChemical Company, Milwaukee, USA) (2.95 g, 18.8 mmol, K₂CO₃ (3.91 g,28.3 mmol), DMA (dimethylacetamide) (45 ml) and toluene (25 ml) in around bottom flask, equipped with Dean-Stark trap, condenser, andnitrogen inlet. Reflux the suspension for 2-3 hours before cooling toambient temperature. Remove the solids via filtration, wash solids withEtOAc, and concentrate the filtrate/wash on a rotary evaporator.Dissolve the remaining oil in EtOAc, wash with water (2×) and brine, dry(MgSO₄) and concentrate. Triturate the resulting brown solid withboiling EtOAc, cool, and collect solid via filtration to give 4.76 g ofthe title compound as a yellow solid. Mass Spectrum (ion spray): m/z=283(M+1); ¹HNMR (DMSO-d₆): 8.56 (s, 1H), 8.25 (d, 1H), 8.02 (s, 1H), 7.52(s, 1H), 7.48 (s, 1H), 7.42 (d, 1H), 7.35 (d, 1H), 7.12 (d, 1H), 2.95(t, 2H), 2.60 (t, 2H), 2.05 (m, 2H).

Intermediate 26-(5-Oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide

Using a method similar to Intermediate 1, using 6-hydroxy-1-tetralone(5.00 g, 30.8 mmol), 6-chloronicotinamide (4.38 g, 28.0 mmol) and K₂CO₃(5.81 g, 42.0 mmol) gives the little compound (5.7 g) as a yellow solid.Mass spectrum (ion spray): m/z=283 (M+1); ¹HNMR (DMSO-d₆): 8.63 (s, 1H),8.29 (d, 1H), 8.06 (s, 1H), 7.90 (d, 1H), 7.51 (s, 1H), 7.16 (d, 1H),7.12 (s, 1H), 7.09 (d, 1H), 2.92 (t, 2H), 2.58 (t, 2H), 2.03 (m, 2H).

Intermediate 36-(5-Oxo-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide

Using a method similar to Intermediate 1, using 5-hydroxy-1-tetralone(2.68 g, 16.5 mmol), 6-chloronicotinamide (2.34 g, 15.0 mmol) and K₂CO₃(3.11 g, 22.5 mmol) gives the title compound (2.34 g) as a yellow solid.Mass spectrum (ion spray): m/z=283 (M+1); ¹HNMR (DMSO-d₆): 8.55 (s, 1H),8.27 (d, 1H), 8.02 (s, 113), 7.80 (m, 1H), 7.48 (s, 1H), 7.43-7.37 (m,1H), 7.14 (d, 1H), 2.66 (t, 2H), 2.58 (t, 2H), 1.96 (m, 2H).

Intermediate 4 6-(1-Oxo-indan-5-yloxy)-nicotinamide

Using a method similar to Intermediate 1, using 5-hydroxy-1-indanone(2.44 g 16.5 mmol), 6-chloronicotinamide (2.34 g, 15.0 mmol) and K₂CO₃(3.11 g, 22.5 mmol) gives the title compound (1.90 g) as a yellow solid.Mass spectrum (ion spray): m/z=269 (M+1); ¹HNMR (DMSO-d₆): 8.63 (s, 1H),8.30 (d, 1H), 8.06 (s, 1H), 7.68 (d, 1H), 7.52 (s, 1H), 7.33 (s, 1H),7.19 (d, 1H), 7.17 (d, 1H), 3.07 (t, 2H), 2.64 (t, 2H).

Intermediate 5 6-(1-Oxo-indan-4-yloxy)-nicotinamide

Using a method similar to Intermediate 1, using 4-hydroxy-1-indanone(2.44 g, 16.5 mmol), 6-chloronicotinamide (234 g, 15.0 mmol) and K₂CO₃(3.11 g, 22.5 mmol) gives the title compound (1.22 g) as a yellow solid.Mass spectrum (ion spray): m/z=269 (M+1); ¹HNMR (DMSO-d₆): 8.57 (s, 1H),8.29 (d, 1H), 8.03 (s, 1H), 7.55-7.46 (M, 4H), 7.19 (d, 1H), 2.81 (t,2H), 2.61 (t, 2H).

Intermediate 6 6-(3-Oxo-indan-5-yloxy)-nicotinamide

Using a method similar to Intermediate 1, using 6-hydroxy-1-indanone (J.Med. Chem. (1998), 41(7), 1068-1083) (2.07 g, 13.9 mmol),6-chloronicotinamide (2.08 g, 13.3 mmol) and K₂CO₃ (2.75 g, 19.9 mmol)gives the title compound (1.36 g) as a yellow solid. Mass spectrum (ionspray): m/z=269 (M+1); ¹HNMR (DMSO-d₆): 8.57 (s, 1H), 8.26 (d, 1H), 8.02(s, 1H), 7.63 (d, 1H), 7.46 (m, 2H), 7.33 (s, 1H), 7.14 (d, 1H), 3.10(t, 2H), 2.68 (t, 2H).

Intermediate 76-(7-Oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide

Combine 7-methoxy-2-tetralone (5.00 g, 28.3 mmol), thiophenol (3.39 g,30.8 mmol), K₂CO₃ (213 mg, 1.54 mmol), and NMP (15 ml) in a round bottomflask equipped with nitrogen inlet. Heat at 180° C. for six hours andthen stir at ambient temperature overnight. Treat reaction mixture with1N aq. NaOH (20 ml) and water (20 ml) before extracting with Et₂O.Adjust the alkaline mixture to pH 4 with 1N aq. HCl and extract withEt₂O (3×). Dry (MgSO₄) the ethereal layer and concentrate to a yellowsolid. Purify the crude material on silica gel, eluting with 5%EtOAc/DCM, to obtain 7-hydroxy-2-tetralone (1.88 g) as a light redsolid. ¹HNMR (CDCl₃): 7.09 (d, 1H), 6.69 (d, 1H), 6.62 (s, 1H), 4.86 (s,1H), 3.53 (s, 2H), 2.99 (t, 2H), 2.54 (t, 2H).

Using a method similar to Example A, using 7-hydroxy-2-tetralone (1.88g, 11.6 mmol), 6-chloronicotinamide (1.81 g, 11.6 mmol) and K₂CO₃ (2.40g, 17.4 mmol) gives the title compound (742 mg), after purification onsilica gel (30% THF/DCM), as an amber foam. Mass spectrum (ion spray):m/z=283 (M+1); ¹HNMR (DMSO-d): 8.57 (s, 1H), 8.23 (d, 1H), 8.01 (s, 1H),7.46 (s, 1H), 7.30 (d, 2H), 7.05 (d, 1H), 6.96 (m, 2H), 3.59 (s, 2H),3.02 (t, 2H), 2.45 (t, 2H).

Intermediate 86-(6-Oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide

Using a method similar to Intermediate 1, using 6-hydroxy-2-tetralone(Journal of Organic Chemistry (1999), 64(26), 9719-9721) (1.55 g, 9.55mmol), 6-chloronicotinamide (1.49 g, 9.55 mmol) and K₂CO₃ (1.98 g, 14.3mmol) gives the title compound (1.32 g), after purification on silicagel (50% THF/DCM), as an amber foam. Mass spectrum (ion spray): m/z=283(M+1); ¹HNMR (DMSO-d₆): 8.59 (s, 1H), 8.23 (d, 1H), 8.01 (s, 1H), 7.47(s, 1H), 7.19 (d, 2H), 7.07 (m, 2H), 6.97 (d, 1H), 3.59 (s, 21), 3.01(t, 2H), 2.43 (t, 2H).

Intermediate 96-(6-Oxo-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide

Using a method similar to Intermediate 1, using 5-hydroxy-2-tetralone(J. Med. Chem. (1978), 21(9), 913-22) (1.98 g, 12.1 mmol),6-chloronicotinamide (1.90 g, 12.1 mmol) and K₂CO₃ (2.52 g, 18.2 mmol)gives the title compound (1.80 g), after purification on silica gel (50%THF/DCM), as an amber foam. Mass spectrum (ion spray): m/z=283 (M+1);¹HNMR (DMSO-d₆): 8.55 (s, 1H), 8.24 (d, 1H), 8.00 (s, 1H), 7.46 (s, 1H),7.25 (d, 2H), 7.08 (m, 2H), 7.00 (d, 1H), 3.64 (s, 2H), 2.77 (t, 2H),2.34 (t, 2H).

Intermediate 106-(7-Oxo-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide

Using a method similar to Intermediate 1, using 8-hydroxy-2-tetralone(J. Med. Chem. (1978), 21(9), 913-22) (1.55 g, 9.55 mmol),6-chloronicotinamide (1.49 g, 9.55 mmol) and K₂CO₃ (1.98 g, 14.3 mmol)gives the title compound (652 mg), after purification on silica gel (50%THF/DCM), as an yellow foam. Mass spectrum (ion spray): m/z=283 (M+1);¹HNMR (CDCl₃): 8.52 (s, 1H), 8.18 (d, 1H), 7.30 (t, 1H), 7.17 (d, 1H),7.02 (m, 2H), 5.92 (broad, 2H), 3.42 (s, 2H), 3.15 (t, 2H), 2.61 (t,2H).

Intermediate 11 6-(3,3-Dimethyl-1-oxo-indan-5-yloxy)-nicotinamide

Add dropwise a solution of BBr₃ (8.14 g, 32.5 mmol) dissolved in DCM (10ml) to a solution of 5-Methoxy-3,3-dimethyl-1-indanone (U.S. Pat. No.6,313,107) (2.47 g, 13.0 mmol) dissolved in DCM (20 ml) and cooled to−78° C. under nitrogen. After stirring at −78° C. for one hour, removethe cold bath and stir at ambient temperature overnight. Cool thereaction mixture to −78° C. and quench with saturated aqueous NaHCO₃.Dilute mixture with water and extract with EtOAc (2×). Wash extractswith water and brine, dry (MgSO₄) and concentrate on rotary evaporatorto a dark amber solid. Triturate the solid with boiling Et₂O, cool, andcollect 5-hydroxy-3,3-dimethyl-1-indanone (1.54 g) as a tan solid.

Add NaH (60%/oil, 196 mg, 4.91 mmol) to a mixture of5-hydroxy-3,3-dimethyl-1-indanone (787 mg, 4.46 mmol) and DMSO (00 ml)sting at ambient temperature under nitrogen. After ten minutes, add6-chloronicotinonitrile (619 mg, 4.46 mmol) dissolved in DMSO (10 ml)and stir the resulting mixture at 60° C. overnight. Quench the reactionwith saturated aqueous NH₄Cl and extract with EtOAc (2×). Wash extractwith water and brine, dry (MgSO₄) and concentrate on rotary evaporatorto a brown, oily solid. Purify on silica gel (10% EtOAc/DCM) to give 877mg of 6-(3,3-Dimethyl-1-oxo-indan-5-yloxy)-nicotinonitrile as a yellowsolid.

Add 30% aqueous H₂O₂ (3.15 ml) to a suspension of6-(3,3-Dimethyl-1-oxo-indan-5-yloxy)nicotinonitrile (877 mg, 3.15 mmol),K₂CO₃ (218 mg, 1.57 mmol) and DMSO (10 ml) stirring under nitrogen atambient temperature. After four hours, dilute the reaction mixture withwater (100 ml) and extract with EtOAc (2×). Wash the extract with waterand brine, dry (MgSO₄) and concentrate on rotary evaporator to yield 876mg of the title compound as an off-white solid. Mass spectrum (ionspray): m/z=297 (M+1); ¹HNMR (CDCl₃): 8.62 (s, 1H), 8.24 (d, 1H), 7.75(d, 1H), 7.24 (s, 1H), 7.14 (d, 1H), 7.07 (d, 1H), 5.91 (broad, 2H),2.63 (s, 2H), 1.43 (s, 6H).

Intermediate 12 6-(4-Methyl-1-oxo-indan-5-yloxy)-nicotinamide

Add dropwise a solution of BBr₃ (14.8 g, 59.1 mmol) dissolved in DCM (50ml) to a solution of 5-Methoxy-4-methyl-1-indanone (Tetrahedron (1970),26(11), 2599-608) (4.17 g, 23.6 mmol) dissolved in DCM (50 ml) andcooled to −78° C. under nitrogen. After stirring at −78° C. for onehour, remove the cold bath and stir at ambient temperature overnight.Cool the reaction mixture to −78° C. and quench with saturated aqueousNaHCO₃. Dilute mixture with water and extract with EtOAc (2×). Washextracts with water and brine, dry (MgSO₄) and concentrate on rotaryevaporator to give 5-hydroxy-4-methyl-1-indanone (2.60 g) as an ambersolid.

Add K₂CO₃ (1.24 g, 9.00 mmol) to a mixture of5-hydroxy-4-methyl-1-indanone (973 mg, 6.00 mmol),6-chloronicotinonitrile (831 mg, 6.00 mmol) and DMSO (15 ml) stirring atambient temperature under nitrogen. Heat the mixture at 55° C. for threedays. Quench the reaction with saturated aqueous NH₄Cl and extract withEtOAc (2×). Wash extract with water and brine, dry (MgSO₄) andconcentrate on rotary evaporator to a brown foam. Purify on silica gel(10% EtOAc/DCM) to give 1.22 g of6-(4-Methyl-1-oxo-indan-5-yloxy)-nicotinonitrile as a yellow solid.

Add 30% aqueous H₂O₂ (3.6 ml) to a suspension of6-(4-Methyl-1-oxo-indan-5-yloxy)-nicotinonitrile (1.22 mg, 4.61 mmol),K₂CO₃ (319 mg, 2.31 mmol) and DMSO (20 ml) stirring under nitrogen atambient temperature. After 2.5 hours, dilute the reaction mixture withwater (100 ml) and extract with EtOAc (2×). Wash the extract with waterand brine, dry (MgSO₄) and concentrate on rotary evaporator to yield1.07 g of the title compound as a yellow solid. Mass spectrum (ionspray): m/z=283 (M+1); ¹HNMR (DMSO-d₆): 8.55 (s, 1H), 8.27 (d, 1H), 8.01(s, 1H), 7.51 (d, 1H), 7.47 (s, 1H), 7.17 (d, 1H), 7.12 (d, 1H), 3.03(t, 2H), 2.66 (t, 2H), 2.07 (s, 3H).

Intermediate 136-(5-Chloro-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide

Add NaBH₄ (79.4 mg, 2.10 mmol) to a suspension of6-(5-Oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy-nicotinamide(Intermediate 2, 395 mg, 1.40 mmol) in MeOH (10 ml), stirring at ambienttemperature. After 24 hours, concentrate the reaction mixture andredissolve in EtOAc. Wash with 5% aqueous KOH, water, and brine beforedrying (MgSO₄) and concentrating to a solid. Purify material on silicagel (50% THF/DCM) to give6-(5-Hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide (288mg) as a white solid. Mass spectrum (ion spray): m/z=285 (M+1); ¹HNMR(CDCl₃): 8.58 (s, 1H), 8.16 (d, 1H), 7.50 (d, 1H), 6.97 (m, 2H), 6.88(s, 1H), 5.95 (broad, 2H), 4.80 (t, 1H), 2.82-2.74 (m, 2H), 2.03-1.77(m, 4H), 1.68 (s, 1H).

Charge flask with 6-(5-Hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yloxy)nicotinamide (288 mg, 1.01 mmol) and SOCl₂ (5 ml) and beat at 50° C.under nitrogen atmosphere with stirring. After 3.5 hours, concentrate onrotary evaporator to give the title compound as a yellow oil. Due toinstability, use this material without purification.

Intermediate 14 6-(1-Chloro-indan-5-yloxy)-nicotinamide

Using a method similar to intermediate 13, using6-(1-Oxo-indan-5-yloxy)-nicotinamide (Intermediate 4, 500 mg, 1.86 mmol)and NaBH₄ (105 mg, 2.79 mmol) gives6-(1-Hydroxy-indan-5-yloxy)-nicotinamide (346 mg) as a white solid. Massspectrum (ion spray): m/z=271 (M+1); ¹HNMR (DMSO-d₆): 8.58 (s, 1H), 8.22(d, 1H), 8.00 (s, 1H), 7.45 (s, 1H), 7.34 (d, 1H), 7.03 (d, 1H), 6.97(s, 1H), 6.93 (d, 1H), 5.03 (t, 1H), 2.93-2.86 (m, 1H), 2.73-2.66 (m,1H), 2.38-2.30 (m, 1H), 1.84-1.72 (m, 1H), 1.33 (s, 1H). Convert6-(1-Hydroxy-indan-5-yloxy)-nicotinamide to the title compound using amethod similar to intermediate 13. Due to instability, use this materialwithout purification.

Intermediate 15 6-(2-Amino-indan-5-yloxy)-nicotinamide

Reflux a mixture of 5-methoxy-2-aminoindane prepared according toHajduk, Philip J., et al.; J. Med. Chem. 1999, 42, 3852-3859. (2.76 g,16.9 mmol) and 48% aqueous HBr for three hours before cooling andconcentrating on rotary evaporator. Treat the crude5-hydroxy-2-aminoindane with THF (50 ml), 1M aqueous K₂CO₃ (42 ml), andBoc₂O (4.05 g, 18.6 mmol) and stir at ambient temperature overnight.Pour mixture into saturated aqueous NH₄Cl and extract with EtOAc (2×).Wash combined extracts with brine, dry (MgSO₄) and concentrate to abrown foam. Purify on silica gel (10% EtOAc/DCM) to giveN-Boc-5-hydroxy-2-aminoindane (2.50 g) as a tan solid.

Combine N-Boc-5-hydroxy-2-aminoindane (2.50 g, 10.0 mmol),6-chloronicotinamide (1.49 g, 9.55 mmol K₂CO₃ (1.90 g, 14.3 mmol), DMA(25 ml) and toluene (20 ml) in a round bottom flask, equipped withDean-Stark trap, condenser, and nitrogen inlet. Reflux the suspensionfor two hours before cooling to ambient temperature. Remove the solidsvia filtration, wash solids with EtOAc, and concentrate thefiltrate/wash on a rotary evaporator. Dissolve the remaining oil inEtOAc, wash with water (2×) and brine, dry (MgSO₄) and concentrate.Purify the material on silica gel (20% THF/DCM) to give[5-(5-carbamoyl-pyridin-2-yloxy)-indan-2-yl]carbamic acid tert-butylester (870 mg) as a light yellow solid.

Add TFA (5.37 g, 47.1 mmol) to a suspension of[5-(5-carbamoyl-pyridin-2-yloxy)-indan-2-yl]-carbamic acid tert-butylester (870 mg, 2.35 mmol) in DCM (30 ml) and stir at ambient temperatureovernight. Concentrate mixture on rotary evaporator and purify on cationexchange column (5 g, Varian) to give the title compound (479 mg) as awhite solid. Mass spectrum (ion spray): m/z=270 (M+1); ¹HNMR (MeOH-d₄):8.61 (s, 113), 8.22 (d, 1H), 7.24 (d, 1H), 6.98 (s, 1H), 6.94 (d, 1H),6.90 (d, 1H), 3.80 (m, 1H), 3.18 (m, 2H), 2.72 (m, 2H).

Intermediate 16 6-(2-Amino-indan-4-yloxy)-nicotinamide

Using a method similar to intermediate 15, using 4-methoxy-2-aminoindane(J. Med. Chem. (1985), 28(4), 515-18, 6.64 g, 40.6 mmol) gives the titlecompound (2.26 g) as a white solid. Mass spectrum (ion spray): m/z=270(M+1); ¹HNMR (CDCl₃): 8.54 (s, 1H), 8.14 (d, 113), 7.23 (t, 1H), 7.12(d, 1H), 6.93 (m, 2H), 6.19 (br s, 2H), 3.81 (m, 1H), 3.22 (dd, 1H),2.94 (dd, 1H), 2.71 (dd, 1H), 2.44 (dd, 1H).

Intermediate 17 6-(1-Aminomethyl-indan-5-yloxy)-nicotinamide

Dissolve sodium metal (1.51 g, 66.0 mmol) in abs. EtOH (50 ml) and DME(100 ml) and add the resulting solution drop-wise to a mixture of5-methoxy-1-indanone (3.57 g, 22.0 mmol), tosylmethyl isocyanide (6.45g, 33.0 mmol) and DME (150 ml) cooled to −5° C. under nitrogen. Afteraddition is complete (ca. one hour), allow mixture to slowly obtainambient temperature and stir overnight. After cooling to 0° C.,carefully quench with water and extract with EtOAc (2×). Wash thecombined extracts with water and brine, dry (MgSO₄) and concentrate.Purify on silica gel (toluene) to give 5-methoxy-indan-1-carbonitrile(2.55 g) as a yellow oil. ¹HNMR (CDCl₃): 7.31 (d, 1H), 6.80 (m, 2H),4.05 (t, 1H), 3.80 (s, 3H), 3.07 (m, 1H), 2.93 (m, 1H), 2.56 (m, 1H),2.39 (m, 1H).

Subject a mixture of 5-methoxy-indan-1-carbonitrile (1.49 g, 8.60 mmol),Raney nickel (500 mg), anhydrous ammonia (10 ml), and abs. EtOH (50 ml)to 900 lbs of hydrogen gas and heat at 80° C. for five hours. Aftercooling and purging with nitrogen, remove the catalyst via filtrationand concentrate the filtrate on a rotary evaporator. Suspend thismaterial in DCM (30 ml) and cool to −78° C. before adding a solution ofBBr₃/DCM (8 ml) dropwise. After the addition is complete, allow themixture to warm to ambient temperature and stir for 2.5 hours. Coolagain to −78° C. and carefully quench with MeOH before concentrating.Treat this material with THF (35 ml), 1M aqueous K₂CO₃ (21.5 ml), andBoc₂O (2.25 g, 10.3 mmol) and stir vigorously at ambient temperatureovernight Pour the reaction mixture into saturated aqueous NH₄Cl andextract with EtOAc (2×). Wash combined extracts with brine, dry (MgSO₄)and concentrate to a yellow foam. Purify on silica gel (10% EtOAc/DCM)to obtain N-Boc-1-aminomethyl-indan-5-ol (945 mg) as a yellow foam.¹HNMR (CDCl₃): 6.98 (d, 1H), 6.85 (s, 1H), 6.73 (s, 1H), 6.65 (d, 1H),4.69 (br s, 1H), 3.45 (m, 1H), 3.22 (m, 2H), 2.88-2.72 (m 2H), 2.20 (m,1H), 1.78 (m, 1H), 1.45 (s, 9H).

Heat a mixture of N-Boc-1-aminomethyl-indan-5-ol (1.13 g, 4.29 mmol),6-chloronicotinamide (671 mg, 4.29 mmol, K₂CO₃ (889 mg, 6.43 mmol), andDMSO (10 ml) at 100° C. for 19 hours. Pour the reaction mixture intosaturated aqueous NH₄Cl and extract with EtOAc. Wash extract with brine,dry (MgSO₄) and concentrate to a brown foam. Purify on silica gel (30%EtOAc/DCM) to obtain[5-(5-carbamoyl-pyridin-2-yloxy)-indan-1-ylmethyl]-carbamic acidtert-butyl ester (847 mg) as a light yellow solid ¹HNMR (CDCl₃): 8.61(s, 1H), 8.17 (d, 1H), 7.24 (d, 1H), 7.00 (s, 1H), 6.95 (m, 3H), 6.03(br s, 2H), 4.65 (br s, 1H), 3.48 (m, 1H), 3.31 (m, 2H), 2.98-2.83 (m,2H), 2.30 (m, 1H), 1.90 (m, 1H), 1.45 (s, 9H).

Add TFA (6.54 g, 57.4 mmol) to a suspension of[5-(5-carbamoyl-pyridin-2-yloxy)-indan-1-ylmethyl]-carbamic acidtert-butyl ester (1.05 g, 2.87 mmol) in DCM (20 ml) and stir at ambienttemperature for four hours. Concentrate mixture on rotary evaporator andpurify on cation exchange column (10 g, Varian) to give the titlecompound (519 mg) as a white solid. Mass spectrum (ion spray): m/z=284(M+1); ¹HNMR (DMSO-d₆): 8.58 (s, 1H), 8.21 (d, 1H), 8.06 (br s, 1H),7.44 (br s, 1H), 7.27 (d, 1H), 7.01 (d, 1H), 6.96 (s, 1H), 6.87 (d, 1H),3.05 (m, 1H), 2.84 (m, 2H), 2.77 (m, 1H), 2.62 (m, 1H), 2.18 (m, 1H),1.82 (m, 1H), 1.71 (br s, 2H).

Intermediate 18 6-(3-Aminomethyl-indan-5-yloxy)-nicotinamide

Using a method similar to intermediate 17, using 6-methoxy-1-indanonegave the title compound as a light yellow solid. Mass spectrum (ionspray): m/z=284 (M+1); ¹HNMR (CDCl₃): 8.59 (s, 1H), 8.15 (d, 1H), 7.25(d, 1H), 7.00 (s, 1H), 6.94 (d, 2H), 6.12 (br s, 2H), 3.23 (m, 1H),2.99-2.84 (m, 4H), 2.33 (m, 1H), 1.89 (m, 1H), 1.40 (br s, 2H).

Intermediate 196-(8-Aminomethyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide

Using a method similar to intermediate 17, using 6-methoxy-1-tetralonegave the title compound as a light amber solid. Mass spectrum (ionspray): m/z=298 (M+1); ¹HNMR (CDCl₃): 8.58 (s, 1H), 8.15 (d, 1H), 7.13(d, 1H), 6.99 (s, 1H), 6.95 (d, 1H), 6.90 (d, 1H), 6.01 (br s, 2H), 2.93(d, 2H), 2.81 (m, 1′, 2.77 (m, 2H), 1.91-1.70 (m, 8H).

Intermediate 206-(5-Aminomethyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide

Using a method similar to intermediate 17, using 5-methoxy-1-tetralonegave the title compound as a light tan solid. Mass sperm (ion spray):m/z=298 (M+1); ¹HNMR (CDCl₃): 8.57 (s, 1H), 8.16 (d, 1H), 7.23-7.12 (m,2H), 6.94-6.90 (m, 2H), 5.83 (br s, 2H), 3.03-2.82 (m, 3H), 2.62-2.47(m, 2H), 1.88-1.66 (m, 4H), 1.34 (br s, 2H).

Intermediate 216-(5-Aminomethyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)nicotinamide

Using a method similar to intermediate 17, using 6-methoxy-1-tetralonegave the title compound as a white foam. Mass spectrum (ion spray):m/z==298 (M+1); ¹HNMR (CDCl₃): 8.59 (s, 1H), 8.16 (d, 1H), 7.25 (d, 1H),6.94 (d, 1H), 6.90 (d, 1H), 6.86 (s, 1H), 5.92 (br s, 2H), 3.00-2.90 (m,2H), 2.85-2.79 (m, 1H), 2.78-2.73 (m, 2H), 1.89-1.69 (m, 4H), 1.34 (brs, 2H).

Intermediate 22[5-(5-Cyano-pyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-carbamicacid tert-butyl ester

Combine N-Boc-1-aminomethyl-indan-5-ol (described in prep forIntermediate 17) (5.80 g, 20.9 mmol), 6-chloronicotinonitrile (2.89 g,20.9 mmol), K₂CO₃ (4.33 g, 31.3 mmol) and DMA (50 ml) and heat at 100 Cfor 4.5 hours. After cooling, pour the reaction mixture into saturated,aqueous NH₄Cl and extract with EtOAc (2×). Wash extract with brine, dry(MgSO₄) and concentrate to a brown foam. Purify on silica gel (30%EtOAc/Hexane) to obtain the title compound (7.88 g) as a light yellowfoam. Mass spectrum (ion spray): m/z=380 (M+1); ¹HNMR (CDCl₃): 8.45 (s,1H), 7.90 (d, 1H), 7.25-7.18 (m, 2H), 6.99 (d, 1H), 6.91 (d, 1H), 4.69(m, 1H), 3.51-3.25 (m, 2H), 3.03 (m, 1H), 2.62-2.39 (m, 1H), 1.83-1.68(m, 4H), 1.46 (s, 9H).

Intermediate 23 4-(1-Oxo-indan-5-yloxy)-benzonitrile

Combine 5-Hydroxyindanone (2.0 g, 13.50 mmol), 4-Fluorobenzonitrile(1.55 g, 12.80 mmol), K₂CO₃ (2.65 g, 19.20 mmol) and toluene/DMA (20ml/40 ml), reflux under Nitrogen using a Dean-Stark Trap. After 4.0hours, cool the reaction to room temperature and add Ethyl Acetate. Washseveral times with 10% LiCl and Brine solution, then dry the organiclayer over Na₂SO₄ follow by concentration. Flash chromatograph using 411then 1/1 hexanes/ethyl acetate eluant to afford 1.64 g, 6.57 mmol (49%yield) of the title compound: ¹H NMR (500 MHz CDCl₃); 2.7-2.8 (2H, m),3.1-3.2 (2H, m), 7.0-7.1 (2H, m), 7.1-7.2 (2H, m), 7.6-7.7 (2H, m),7.7-7.8 (1H, m); MS m/z 250 (M+1).

Intermediate 24 4-(1-Oxo-indan-5-yloxy)-benzamide

Combine 4-(1-Oxo-indan-5-yloxy)-benzonitrile (1.64 g, 6.58 mmol),tert-butyl alcohol (50 ml), and grounded KOH (1.85 g, 32.89 mmol) atroom temperature under nitrogen atmosphere, Stir the reaction for 24hours then concentrate under reduced pressure. Add Ethyl acetate to thereaction mixture and wash with brine. Dry the organic layer over Na₂SO₄.A yellow-mange solid precipitates out to afford 101.0 mg, 0.38 mmol(5.7% yield) of the title compound: No Characterization—Characterized bysequential reaction.

Intermediate 254-(5-Oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-benzonitrile

Combine 6-Hydroxytetralone (4.42 g, 27.24 mmol), 4-Fluorobenzonitrile(3.0 g, 24.76 mmol), K₂CO₃ (5.1 g, 37.14 mmol) and toluene/DMA (30 ml/90ml), then reflux under nitrogen using a Dean Stark Trap. After 4 hours,cool the reaction to room temperature and add to a separatory funnel.Add Ethyl acetate and wash the organic layer several times with water,then a brine solution, and dry the organic layer over Na₂SO₄. Flashchromatograph using 4/1 hexanes/ethyl acetate eluant to afford 5.34 g,20.3 mmol (82% yield) of the title compound: ¹H NMR (500 MHz, CDCl₃);2.1-2.2 (2H, m), 2.6-2.7 (2H, m), 2.9-3.0 (2H, m), 6.85 (1H, s), 6.9-7.0(1H, m), 7.05-7.15 (2H, m), 7.6-7.7 (2H, m), 8.05-8.10 (1H, m); MS m/z264 (M+1).

Intermediate 264-(5-Oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-benzamide

Combine 4-(5-Oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-benzonitrile(5.34, 20.3 mmol), t-butyl alcohol (100 ml), and KOH (5.7 g, 101.5mmol). After the reaction stirs for 72 hours at room temperature,concentrate under reduced pressure and then add ethyl acetate. Wash theorganic phase with water, a brine solution, and then dry the organiclayer over Na₂SO₄. Flash chromatograph using 2/1 CH₂Cl₂/ethyl acetateeluent to afford 5.20 g, 18.5 mmol (91% yield) of the title compound: ¹HNMR (500 MHz, CDCl₃); 2.1-2.2 (2H, m), 2.6-2.7 (2H, m), 2.9-3.0 (2H, m),5.6-6.2 (2H, br m); 6.85 (1H, s), 6.9-7.0 (1H, m), 7.05-7.15 (2H, m),7.8-7.9 (2H, m) 8.05-8.10 (1H, m); MS m/z 284 (M+3).

Intermediate 27 6-Methoxy-1-oxo-indan-2-carboxylic acid methyl ester

Combine NaH (5.4 g, 122.1 mmol), THF anhydrous (150 mL), anddimethylcarbonate (6.6 mL, 81.3 mmol). While refluxing the reactionunder a nitrogen atmosphere, add dropwise 5-Methoxyindanone (3.46 g,21.33 mmol) over one hour. After the reaction mixture refluxes for 12hours, quench using Acetic acid and then add Ethyl acetate to thereaction mixture in a separatory funnel. Wash the organic layer severaltimes with water and dry the organic layer over Na₂SO₄ followed byconcentration under reduced pressure. Flash Chromatograph using 1:1Hexanes:Ethyl acetate to afford 3.14 g, 14.3 mmol (67% yield) of thetitle compound: ¹H NMR (500 MHz, CDCl₃); 3.3-3.4 (1H, dd), 3.5-3.6 (1H,dd), 3.7-3.8 (1H, m), 3.8 (3H, s), 3.9 (3H, s), 6.8-7.0 (2H, m), 7.7-7.8(1H, m); TLC 2:1 Hexanes:Ethyl acetate R_(f)=0.4.

Intermediate 28 5-Methoxy-indan-2-carboxylic acid methyl ester

Combine in a Parr shaker 6-Methoxy-1-oxo-indan-2-carboxylic acid methylester (3.14 g, 14.25 mmol), added acetic acid (150 mL), perchloric acid(0.8 mL) and 5% Pd—C (0.14 mmol). After the reaction has been on theparr shaker under 40 atm of H₂ pressure at room temperature for 12hours, filter the reaction mixture through a pad of Celite using ethylacetate eluent. Then add the filtrate to a separatory funnel and washwith water then brine, and dry the organic layer over Na₂SO₄. Afterconcentrating under reduced pressure, flash Chromatograph using 8:1Hexanes:Ethyl acetate to afford 1.9 g, 9.21 mmol (65% yield) of thetitle compound as a clear oil: ¹H NMR (500 MHz, CDCl₃); 3.2-3.4 (5H, m),3.7 (3H, s), 3.8 (3H, s), 6.7-6.8 (2H, m), 7.1-7.2 (1H, m); TLC 1:1Hexanes:Ethyl acetate R_(f)=0.6.

Intermediate 29 (5-Methoxy-indan-2-yl)-methanol

Combine 5-Methoxy-indan-2-carboxylic acid methyl ester (Intermediate 28,1.90 g, 9.21 mmol), LiAlH₄ (0.70 g, 18.43 mmol), and THF anhydrous (60ml). After the reaction stirs under a nitrogen atmosphere at roomtemperature for 2 hours, quench the reaction mixture with 5 mL ofdeionized water. Filter the mixture through a pad of Celite using EtOAceluent, and wash the organic layer with brine, and dry over Na₂SO₄.After concentrating under reduced pressure, the flash chromatograph themixture to afford 1.43 g, 8.0 mmol (87% yield) of the title compound asa clear oil: ¹H NMR (500 MHz, CDCl₃); 1.4-1.6 (1H, br s), 2.6-2.8 (3H,m), 2.9-3.2 (2H, m), 3.6-3.7 (2H, m), 3.8 (3H, s), 6.7-6.8 (2H, m),7.1-7.2 (1H, m); TLC 1:1 Hexanes:Ethyl acetate R_(f)=0.4.

Intermediate 30 2-Hydroxymethyl-indan-5-ol

Combine (5-Methoxy-indan-2-yl)-methanol (117.0 mg, 0.65 mmol), and 48%HBr (aq). After the reaction refluxes for 30 minutes, cool to roomtemperature and extract the product with ethyl acetate. Wash with brineand dry over Na₂SO₄. After concentrating the organic layer under reducedpressure, flash chromatograph using 2/1 Hexanes/Ethyl acetate eluent toafford 67.3 mg, 0.41 mmol (63% yield) of the title compound: ¹H NMR (500MHz, CDCl₃); 2.6-2.8 (3H, m), 2.9-3.1 (2H, m), 3.6-3.8 (2H, m), 6.6-6.8(2H, m), 7.0-7.1 (1H, m); TLC 1:1 Hexanes:Ethyl acetate R_(f)=0.3.

Intermediate 31 6-(2-Hydroxymethyl-indan-5-yloxy)nicotinamide

Combine in a round bottom flask equipped with a stir, Dean Stark Trapfilled with toluene, and reflux condenser 2-Hydroxymethyl-indan-5-ol(630.2 mg, 3.84 mmol), K₂CO₃ (690.0 mg, 5.0 mmol), 6-Chloronicotinamide(600.0 mg, 3.84 mmol) and a solution of DMA:Toluene (15:5 mL). After thereaction refluxes under nitrogen atmosphere for 5 hours, concentrateunder reduced pressure and then add ethyl acetate. Wash the organiclayer several times with water, then brine, and dry over Na₂SO₄. Afterconcentrating the reaction mixture under reduced pressure, flashchromatograph using 20% THF, 7% 1N NH₃-MeOH, 73% DCM eluent to afforded481.1 mg, 1.69 mmol (44% yield) of the title compound: ¹H NMR (500 MHz,CDCl₃); 1.8-2.2 (4H, m), 2.6-2.8 (3H, m), 3.6-3.8 (2H, br d), 3.9-4.0(1H, m), 6.1-6.6 (2H, br d), 6.8-7.0 (3H, m), 7.2-7.3 (1H, m), 8.1-8.2(1H, m), 8.6 (1H, s); MS m/z 285 (M+1).

Intermediate 32 6-(2-Formyl-indan-5-yloxy)-nicotinamide

Combine DCM (3 mL) and oxalyl chloride (41 uL) under nitrogen atmosphereat −78° C., and then add DMSO (49 uL) in DCM (2 mL). After the solutionstirs for 15 minutes, add 6-(2-Hydroxymethyl-indan-5-yloxy)nicotinamide(33.1 mg, 0.116 mmol) in DCM (2 mL). After 15 minutes, add Et₃N (97 uL,0.70 mmol). After the reaction gradually warms to room temperature overthe next 5 hours, then quench with water. Add the mixture to aseparatory funnel and extract the product with DCM. Wash the organicphase with brine and then dry over Na₂SO₄. After concentrating underreduced pressure, flash chromatograph using 10% THF/CH₂Cl₂ eluentaffords 27.4 mg, 0.10 mmol (84% yield) of the title compound: ¹H NMR(500 MHz, CDCl₃); 3.1-3.2 (2H, m), 3.2-3.4 (3H, m), 6.8-7.0 (4H, m),7.1-7.3 (1H, m), 8.8-8.9 (1H, m), 8.4 (1H, s), 9.7 (1H, s); TLC 1:6THF:CH₂Cl₂R_(f)=0.7.

Intermediate 33 2-Tert-butyldimethylsilyloxyphenethyl amine

To a solution of TBDMSCl (2.1 equiv) and DBU (2.1 equiv) in CH₂Cl₂ (0.5M), add the alcohol (1 equiv). Stir the resulting reaction mixture underN₂ at room temperature 3 hours. Wash the reaction mixture with water,0.5% HCl and saturated aqueous solution of NaHCO₃, separate the organiclayer, and dry over anhydrous NaSO₄. Evaporation of the solvent yields aresidue which is purified by flash chromatography using EtOAc/CH₂Cl₂/2MNH₃ in methanol, 0.6/0.35/1.05) to afford the title compound.

92% Yield.

¹H NMR(CHCl₃-d₃) δ: 729 (s, 5H), 4.65 (t, 1H, J=5.4 Hz), 2.83 (d, 2H,J=5.4 Hz), 1.40 (bs, 2H), 0.91 (s, 9H), 0.05 (s, 3H), −0.10 (s, 3H).

Intermediate 346-{5-[2-(tert-Butyl-dimethyl-silanyloxy)-2-phenyl-ethylamino]-5,6,7,8-tetrahydro-naphthalen-2-yloxy}-nicotinamide

The compound is prepared according to General Procedure IV and usedwithout further purification in the synthesis of example 219.

Intermediate 35Benzyl-(2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-amine

Dissolve 2-Methoxy-5,7,8,9-tetrahydro-benzocyclohepten-6-one (preparedaccording to JCS Perkin Trans. 1, 1992, 1475-1481, 83 mg, 0.44 mmol) in1 mL of 19:1 methanol/acetic acid as solvent, and treat the solutionwith benzylamine (60 uL, 65 mg, 0.60 mmol) and NaCNBH₃ (80 mg, 1.27mmol). Agitate the reaction mixture overnight, then dilute with 25 mLdichloromethane. Wash the organic layer with 25 mL 10%/aqueous potassiumcarbonate solution, the 25 mL brine, dry over MgSO₄ and evaporate toyield 103 mg product, used in subsequent chemistry without furtherpurification; 80% crude yield.

¹H NMR (CDCl₃): 7.2-7.4: m, 5H, 7.15: m, 1H, 6.6-6.7: m, 2H, 3.8-3.9: m,2H, 3.78: s, 3H, 2.9: m, 2H, 2.65-2.8: m, 3H, 1.5-2.05: ma, 5H.

Intermediate 36(2-Methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-phenethyl-amine

The compound is prepared analogously to Intermediate 35 usingphenethylamine and was used in subsequent chemistry without furtherpurification, 76% crude yield.

¹H NMR (CDCl₃): 7.15-7.35: m, 5H, 7.03: m, 1H, 6.03: m, 2H, 3.79: s, 3H,2.6-3.0: m, 8H, 1.4-2.0: m, 5H.

Intermediate 37Benzyl-(2-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-carbamicacid tert-butyl ester

Intermediate 35 (100 mg, 0.35 mmol) is dissolved in 10 mL 48% aqueousHBr and heated under reflux for 2 hours. The reaction is then cooled toroom temperature and stirred overnight, then the solvent is removedunder reduced pressure. The residue is dissolved in 4-mL dioxane/1 mL 1Naqueous NaOH, and BOC anhydride (100 mg, 0.46 mmol) is added and thebiphasic reaction mixture is stirred for 9 days at room temperature. Andadditional portion of BOC anhydride (100 mg, 0.46 mmol) is added and thereaction is stirred for 2 days at room temperature. The reaction is thenpoured into 25 mL saturated aqueous NH₄Cl, and the aqueous phase isextracted with 25 mL CH₂Cl₂. The organic layer is dried over MgSO₄ andevaporated, and the residue is purified by flash chromatography (20%Ethyl acetate/hexanes) to yield 30 mg of the desired material; 23% yieldfrom Intermediate 35.

Intermediate 38(2-Hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-phenethyl-carbamicacid tert-butyl ester

The compound is pod analogously to Intermediate 37 starting fromintermediate 36; 23% yield from Intermediate 36.

Agitate (orbital shaker) a 4 ml screw-cap vial charged with molecularsieves (ca. 200 mg), a solution of amine (0.10 M/MeOH, 100 umol, 1000uL) and a solution of aldehyde (1.0 M/MeOH, 200 mmol, 200 uL) at ambienttemperature overnight. Treat mixture with a solution of NaBH₃CN (0.50M/MeOH, 250 umol, 500 uL) and agitate an additional three hours. Removethe molecular sieves via filtration and concentrate the filtrate under anitrogen stream. Redissolve the filtrate in 5% AcOH/MeOH and purify oncation exchange resin (500 mg, Varian). Further purify products onreverse-phase-HPLC (C18 column, 10% ACN/water (0.01% TFA buffer) to 95%ACN/water over 15 minutes) and free-base on cation exchange.

gitate (orbital shaker) a 4 ml screw-cap vial charged with amine (120umol), a solution or suspension of ketone (0.10M/THF, 100 umol, 1000uL), and solution of Ti(^(i)PrO)₄ (0.40 M/THF, 200 umol, 500 uL) atambient temperature overnight. Treat the reaction with a 1.0M TiCl₄/DCMsolution (200 umol, 200 uL) and agitate for an additional eight hoursbefore adding NaBH₃CN (0.50 M/MeOH, 200 umol, 400 uL) and agitatingovernight. Quench the reaction with 2N aq. NaOH (1 ml), agitate for onehour and spin down on centrifuge. Decant off supernate and concentratesupernate under nitrogen stream. Redissolve the filtrate in 5% AcOH/MeOHand purify on cation exchange resin (500 mg, Varian). Further puntproducts on reverse-phase HPLC (C18 column, 10% ACN/water (0.01% TFAbuffer) to 95% ACN/water over 15 minutes) and free-base on cationexchange.

gitate (orbital shaker) a 4 ml screw-up vial charged with amine (120umol), K₂CO₃ (34 mg, 250 umol), NaI (3 mg, 20 umol), and a suspension ofcrude alkyl chloride (0.05M/CAN, 100 umol, 2000 uL) at ambienttemperature overnight. Remove the solids via filtration and concentratethe filtrate under a nitrogen stream. Redissolve the filtrate in 5%AcOH/MeOH and purify on cation exchange resin (500 mg, Varian). Furtherpurify products on reverse-phase HPLC(C18 column, 10% ACN/water (0.01%TFA buffer) to 95% ACN/water over 15 minutes) and free-base on cationexchange.

Add Ti(O^(i)Pr)₄ (2 equiv) to a mixture of amine (1.5 equiv), ketone (1equiv) in THF (0.04 M) is added at 0° C. and stir the resulting reactionmixture overnight under nitrogen atmosphere at room temperature. Thefollowing day add 1.0 M solution of TiCl₄ in CH₂Cl₂ (2 equiv), and after2.5 hours add NaCNBH₄ (2 equiv) and stir the reaction mixture for 2hours, then quench with saturated aqueous solution of NaHCO₃ dilutedwith ethyl acetate. Filter off the solid and separate the organic layer,dry over anhydrous Na₂SO₄ and evaporate the solvent to yield a residuewhich is purified by flash chromatography using EtOAc/CH₂Cl₂/2M NH₃ inmethanol, 0.6/0.3510.05) to afford the title compound as a white solid.

Example 1 6-[1-(3-Methyl-butylamino)-indan-5-yloxy]-nicotinamide

Add Ti(^(i)PrO)₄ (1.70 g, 6.00 mmol) to a suspension of6-(1-oxo-indan-5-yloxy)nicotinamide (Intermediate 4, 805 mg, 3.00 mmol),isoamyl amine (314 mg, 3.60 mmol) and THF (10 ml) and stir overnightunder a nitrogen atmosphere at ambient temperature. Treat the reactionmixture with a solution of TiCl₄ (1.0M/DCM, 6.00 ml, 6.00 mmol) and stirat ambient temperature for three hours before adding NaBH₃CN (377 mg,6.00 mmol) dissolved in MeOH (5 ml). After an additional three hours,quench the reaction with 2N aq. NaOH, making the suspension basic. Stirthe suspension for one hour and filter through a filter aid to removesolids, washing them with EtOAc. Separate layers in the filtrate/washand wash the organic layer with brine before drying (MgSO₄) andconcentrating. Purify on silica gel (5% (1N NH₃/MeOH)/45% EtOAc/DCM) toobtain 491 mg of the title compound as a light yellow solid. Massspectrum (ion spray): m/z=340 (M+1); ¹HNMR (CDCl₃): 8.59 (s, 1H), 8.16(d, 1H), 7.39 (d, 1H), 7.00 (s, 1H), 6.97-6.94 (m, 2H), 5.87 (br. s,2H), 4.25 (t, 1H), 3.02 (m, 1H), 2.83 (m, 1H), 2.75 (t 2H), 2.46 (m,1H), 1.89 (m, 1H), 1.67 (m, 1H), 1.44 (m, 2H), 0.92 (d, 6H).

Example 2 6-[1-(2-Thiophen-2-yl-ethylamino)-indan-5-yloxy]-nicotinamide

Using a method similar to Example 1, using6-(1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 4, 268 mg, 1.00mmol), 2-thiopheneethylamine (152 mg, 1.20 mmol), Ti(^(i)PrO)₄ (568 mg,2.00 mmol), TiCl₄ (1.0M/DCM, 2.00 ml, 2.00 mmol), and NaBH₃CN (125 mg,2.00 mmol) gives the title compound (196 mg) as a white solid. Massspectrum (ion spray): m/z=380 (M+1); ¹HNMR (CDCl₃): 8.58 (s, 1H), 8.15(d, 1H), 7.35 (d, 1H), 7.16 (d, 1H); 6.99 (s, 1H), 6.96-6.93 (m, 3H),6.86 (d, 1H), 5.81 (br. s, 2H), 4.28 (t, 1H), 3.11-2.96 (m, 5H), 2.83(m, 1H), 2.46 (m, 1H), 1.87 (m, 1H).

Example 36-{1-[2-(4-Methoxy-benzo[b]thiophen-3-yl)-ethylamino]-indan-5-yloxy}-nicotinamide

Using a method similar to Example 1, using 6-(1oxo-indan-5-yloxy)nicotinamide (Intermediate 4, 97 mg, 0.362 mmol),2-(4-methoxy-benzo[b]thiophen-3-yl)-ethylamine HCl salt (J. Heterocycl.Chem. (1973), 10(3), 297-305, 93 mg, 0.435 mmol), Et₃N (44 mg, 0.435mmol), Ti(^(i)PrO)₄ (206 mg, 0.725 mmol), TiCl₄ (1.0M/DCM, 0.725 ml,0.725 mmol), and NaBH₃CN (45 mg, 0.725 mmol) gives the title compound(83 mg) as a light yellow solid. Mass spectrum (ion spray): m/z=460(M+1); ¹HNMR (CDCl₃): 8.58 (s, 1H), 8.15 (d, 1H), 7.42 (d, 1H), 7.33 (d,1H), 7.25 (t, 1H), 7.02 (s, 1H), 6.98 (s, 1H), 6.94-6.91 (m, 2H), 6.75(d, 1H), 5.82 (br. s, 2H), 4.30 (t, 1H), 3.91 (s, 3H), 3.29 (t, 2H),3.09 (m, 2H), 3.01 (m, 1H), 2.83 (m, 1H), 2.45 (m, 1H), 1.90 (m, 1H).

Example 46-[5-(2-Thiophen-2-yl-ethylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide

Using a method similar to Example 1, using6-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide(intermediate 2, 546 mg, 2.00 mmol), 2-thiopheneethylamine (305 mg, 2.40mmol), Ti(PrO)₄ (1.14 g, 4.00 mmol), TiCl₄ (11.0M/DCM, 4.00 ml, 4.00mmol), and NaBH₃CN (251 mg, 4.00 mmol) gives the title compound (491 mg)as a light yellow solid. Mass spectrum (ion spray): m/z=394 (M+1); ¹HNMR(CDCl₃): 8.58 (s, 1H), 8.15 (d, 1H), 7.36 (d, 1H), 7.15 (d, 1H),6.95-6.89 (m, 3H), 6.85 (m, 2H), 5.87 (br. s, 2H), 3.81 (t, 1H),3.12-3.02 (m, 3H), 2.98 (m, 1H), 2.83-2.68 (m, 2H), 1.98-1.82 (m, 3H),1.73 (m, 1H).

Example 56-{1-[2-(3-Chloro-phenyl)-ethylamino]-indan-5-yloxy}-nicotinamide

Using a method similar to Example 1, using6-(1-oxo-indan-5-yloxy)nicotinamide (Intermediate 4, 905 mg, 3.00 mmol),2-(3-chlorophenyl)ethylamine (560 mg, 3.60 mmol), Ti(^(i)PrO)₄ (1.70 g,6.00 mmol), TiCl₄ (1.0M/DCM, 6.00 ml, 6.00 mmol), and NaBH₃CN (377 mg,6.00 mmol) gives the title compound (738 mg) as a white solid. Massspectrum (ion spray): m/z=408 (M+1); ¹HNMR (CDCl₃): 8.58 (s, 1H), 8.15(d, 1H), 7.31 (d, 1H), 7.25-7.18 (m, 3H), 7.11 (d, 1H), 6.98-6.93 (m,3H), 5.89 (br. s, 2H), 4.26 (t, 1H), 3.03-2.96 (m, 3H), 2.87-2.78 (m,3H), 2.44 (m, 1H), 1.85 (m, 1H).

Example 66-{5-[2-(3-Chloro-phenyl)-ethylamino]-5,6,7,8-tetrahydro-naphthalen-2-yloxy}-nicotinamide

Using a method similar to Example 1, using6-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide(Intermediate 2, 846 mg, 3.00 mmol), 2-(3-chlorophenyl)ethylamine (560mg, 3.60 mmol), Ti(^(i)PrO)₄ (1.70 g& 6.00 mmol), TiCl₄ (1.0M/DCM, 6.00ml, 6.00 mmol), and NaBH₃CN (377 mg, 6.00 mmol) gives the title compound(1.16 g) as a white solid. Mass spectrum (ion spray): m/z=422 (M+1);¹HNMR (CDCl₃): 8.58 (s, 1H), 8.15 (d, 1H), 7.33 (d, 1H), 7.24-7.17 (m,3H), 7.11 (d, 1H), 6.94 (d, 1H), 6.90 (d, 1H), 6.85 (s, 1H), 5.87 (br.s, 2H), 3.79 (t, 1H), 3.06-2.91 (m, 2H), 2.83-2.67 (m, 4H), 1.97-1.79(m, 3H), 1.73 (m, 1H).

Example 76-{1-[2-(2-Fluoro-phenyl)-ethylamino]-indan-5-yloxy}-nicotinamide

Using a method similar to Example 1, using6-(1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 4, 805 mg, 3.00mmol), 2-(2-fluorophenyl)ethylamine (501 mg, 3.60 mmol), Ti(^(i)PrO)₄(1.70 g, 6.00 mmol), TiCl₄ (1.0M/DCM, 6.00 ml, 6.00 mmol), and NaBH₃CN(377 mg, 6.00 mmol) gives the title compound (398 mg) as a white solid.Mass spectrum (ion spray): m/z=392 (M+1); ¹HNMR (CDCl₃): 8.58 (s, 1H),8.15 (d, 1H), 7.32 (d, 1H), 7.25-7.17 (m, 2H), 7.09-7.00 (m, 2H), 6.98(s, 1H), 6.94 (d, 2H), 5.93 (br. s, 2H), 4.28 (t, 1H), 3.04-2.95 (m,3H), 2.92-2.87 (m, 2H), 2.83 (ma, 1H), 2.45 (m, 1H), 1.85 (m, 1H).

Example 36-{5-[2-(2-Fluoro-phenyl)-ethylamino]-5,6,7,8-tetrahydro-naphthalen-2-yloxy}-nicotinamide

Using a method similar to Example 1, using6-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide(Intermediate 2, 846 mg, 3.00 mmol), 2-(2-fluorophenyl)ethylamine (501mg, 3.60 mmol), Ti(^(i)PrO)₄ (1.70 g, 6.00 mmol), TiCl₄ (1.0M/DCM, 6.00ml, 6.00 mmol), and NaBH₃CN (377 mg, 6.00 mmol) gives the title compound(1.01 g) as 8 white solid. Mass spectrum (ion spray): m/z=406 (M+1);¹HNMR (CDCl₃): 8.59 (s, 1H), 8.15 (d, 1H), 7.35 (d, 1H), 7.26-7.16 (m,2H), 7.09-6.99 (m, 2H), 6.93 (d, 1H), 6.89 (d, 1H), 6.84 (s, 1H), 5.89(br. s, 2H), 3.81 (t, 1H), 3.07-2.85 (m, 4H), 2.83-2.67 (m, 2H),1.98-1.80 (m, 3H), 1.73 (m, 1H).

Example 9 6-[1-(2,2-Diphenyl-ethylamino)-indan-5-yloxy]-nicotinamide

Using a method similar to Example 1, using6-(1-oxo-indan-5-yloxy)nicotinamide (Intermediate 4, 536 mg, 2.00 mmol),2,2-diphenylethylamine (473 mg, 2.40 mmol), Ti(^(i)PrO)₄ (1.14 g, 4.00mmol), TiCl₄ (1.0M/DCM, 4.00 ml, 4.00 mmol), and NaBH₃CN (251 mg, 4.00mmol) gives the title compound (608 mg) as a white solid. Mass spectrum(ion spray): m/z=450 (M+1); ¹HNMR (CDCl₃): 8.57 (s, 1H), 8.14 (d, 1H),7.33-7.18 (m, 1H), 6.98-6.90 (m, 3H), 5.85 (br. s, 2H), 4.33-4.23 (m,2H), 3.41-3.31 (m, 2H), 2.95 (m, 1H), 2.81 (m, 1H), 2.46 (m, 1H), 1.85(m, 1H).

Example 106-[5-(3-Phenyl-propylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide

Using a method similar to Example 1, using6-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide(Intermediate 2, 564 mg, 2.00 mmol), 3-phenylpropylamine (324 mg, 2.40mmol), Ti(^(i)PrO)₄ (1.14 g, 4.00 mmol), TiCl₄ (1.0M/DCM, 4.00 ml, 4.00mmol), and NaBH₃CN (251 mg, 4.00 mmol) gives the title compound (558 mg)as a light yellow solid. Mass spectrum (ion spray): m/z=402 (M+1); ¹HNMR(CDCl₃): 8.59 (s, 1H), 8.14 (d, 1H), 7.40 (d, 1H), 7.30-7.25 (m, 2H),7.21-7.16 (m, 3H), 6.93 (d, 1H), 6.91 (d, 1H), 6.85 (s; 1H), 5.99 (br.s, 2H), 3.74 (t, 1H), 2.84-2.64 (m, 6H), 2.00-1.79 (m, 5H), 1.72 (m,1H).

Example 11 6-[1-(3-Phenyl-propylamino)-indan-5-yloxy)-nicotinamide

Using a method similar to Example 1, using6-(]-oxo-indan-5-yloxy-nicotinamide (Intermediate 4, 805 mg, 3.00 mmol),3-phenylpropylamine (486 mg, 3.60 mmol), Ti(^(i)PrO)₄ (1.70 g, 6.00mmol), TiCl₄ (1.0M/DCM, 6.00 ml, 6.00 mmol), and NaBH₃CN (377 mg, 6.00mmol) gives the title compound (681 mg) as a light yellow solid. Massspectrum (ion spray): m/z=388 (M+1); ¹HNMR (CDCl₃): 8.59 (s, 1H), 8.15(d, 1H), 7.35 (d, 1H), 7.30-7.25 (m, 2H), 7.22-7.16 (m, 3H), 6.99 (s,1H), 6.95 (d, 1H), 5.85 (br. s, 2H), 4.23 (t, 1H), 3.00 (m, 1H), 2.83(m, 1H), 2.78 (t, 2H), 2.70 (m, 2H), 2.43 (m, 1H), 1.87 (m, 3H).

Example 12 6-(1-Hexylamino-indan-5-yloxy)-nicotinamide

Using a method similar to Example 1, using6-(1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 4, 1.11 g, 4.14mmol), n-hexylamine (502 mg, 4.96 mmol), Ti(^(i)PrO)₄ (2.35 g, 8.27mmol), TiCl₄ (1.0M/DCM, 8.27 ml, 8.27 mmol), and NaBH₃CN (520 mg, 8.27mmol) gives the title compound (495 mg) as a tan solid. Mass spectrum(ion spray): m/z=354 (M+1); (HNMR (CDCl₃): 8.59 (s, 1H), 8.16 (d, 1H),7.38 (d, 1H), 6.99 (s, 1H), 6.96 (d, 1H), 6.94 (d, 1H), 5.92 (br. s, 2M,4.24 (t, 1H), 3.01 (m, 1H), 2.83 (m, 1H), 2.73 (t, 2H), 2.45 (m, 1H),1.88 (m, 1H), 1.53 (m, 3H), 1.32 (m, 5H), 0.89 (t, 3H).

Example 136-{1-[(2,2-Diphenyl-ethyl)-methyl-amino]-indan-5-yloxy}-nicotinamide

Add paraformaldehyde (57 mg) and NaBH₃CN (46 mg, 0.734 mmol) to asolution of 6-[1-(2,2-Diphenyl-ethylamino)-indan-5-yloxy]-nicotinamide(example 9, 110 mg, 0.245 mmol) in 5% AcOH/MeOH (3 ml) and stir atambient temperature for two days. Concentrate the reaction mixture andpartition remaining residue between EtOAc and 1M aq. K₂CO₃. Separatelayers and wash organic with 1M aq. K₂CO₃ and brine before dying (MgSO₄)and concentrating. Purify on silica gel (5% (1N NH₃/MeOH)/45% EtOAc/DCM)to obtain 74 mg of the title compound as a white solid. Mass spectrum(ion spray): m/z=464 (M+1); ¹HNMR (CDCl₃): 8.54 (s, 1H), 8.15 (d, 1H),7.30-7.15 (m, 10H), 6.95-6.81 (m, 4H), 5.81 (br. s, 2H), 4.39 (t, 1H),4.20 (t, 1H), 3.02 (d, 2H), 2.94-2.75 (m, 2H), 2.27 (s, 3H), 2.06 (m,2H).

Example 14 6-[1-(2-m-Tolyl-ethylamino)-indan-5-yloxy]-nicotinamide

Add Ti(^(i)PrO)₄ (1.70 g, 6.00 mmol) to a suspension of6-(1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 4, 805 mg, 3.00mmol), 2-(3-methylphenyl)ethylamine (446 mg, 3.30 mmol) and THF (20 ml)and stir for six hours under a nitrogen atmosphere at ambienttemperature. After cooling in an ice/water bath, treat the reactionmixture with a solution of TiCl₄ (1.0M/DCM, 6.00 ml, 6.00 mmol) and stirat 0-5° C. for two hours before adding NaBH₃CN (377 mg, 6.00 mmol)dissolved in MeOH (5 ml). Allow the reaction mixture to warm to ambienttemperature as the cold bath warms and stir overnight. Quench thereaction with 2N aq. NaOH, making the suspension basic. Stir thesuspension for one hour and filter through a filter aid to removesolids, washing them with EtOAc. Separate layers in the filtrate/washand wash the organic layer with brine before drying (MgSO₄) andconcentrating. Purify on silica gel (5% (1N NH₃/MeOH)/45% EtOAc/DCM) toobtain 849 mg of the title compound as a light yellow solid. Massspectrum (ion spray): m/z=388 (M+1); ¹HNMR (CDCl₃): 8.59 (s, 1H), 8.15(d, 1H), 7.30 (d, 1H), 7.19 (t, 1H), 7.05-7.01 (m, 3H), 6.98 (s, 1H),6.93 (d, 2H), 5.96 (br. s, 2H), 4.26 (t, 1H), 3.02-2.94 (m, 3H),2.86-2.76 (m, 3H), 2.44 (m, 1H), 2.33 (s, 3H), 1.84 (m, 1H).

Example 15 6-[1-(Hexyl-methyl-amino)-indan-5-yloxy]-nicotinamide

2103035. AG2-A02084-114.

Using a method similar to Example 13, using6-(1-hexylamino-indan-5-yloxy)-nicotinamide (example 12, 490 mg, 1.38mmol), paraformaldehyde (443 mg), and NaBH₃CN (261 mg, 4.16 mmol) givesthe title compound (373 mg) as a light yellow solid. Mass spectrum (ionspray): m/z=368 (M+1); ¹HNMR (CDCl₃): 8.59 (s, 1H), 8.16 (d, 1H), 7.38(d, 1H), 6.98-6.93 (m, 3H), 5.89 (br. s, 2H), 4.42 (t, 1H), 2.97-2.78(m, 2H), 2.40 (m, 2H), 2.22 (s, 3H), 2.08 (m, 2H), 1.51 (m, 2H),1.36-1.22 (m, 6H), 0.88 (t, 3H).

Example 16 6-[1-(2-Cyclohexyl-ethylamino)-indan-5-yloxy]-nicotinamide

Using a method similar to Example 14, using6-(1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 4, 536 mg, 2.00mmol), 2-cyclohexylethylamine HCl ((Synthesis (1983), (5), 388-9), 393mg, 2.40 mmol), Et₃N (243 mg, 2.40 mmol), Ti(^(i)PrO)₄ (1.14 g, 4.00mmol), TiCl₄ (11.0M/DCM, 4.00 ml, 4.00 mmol), and NaBH₃CN (251 mg, 4.00mmol) gives the title compound (628 mg) as a yellow solid. Mass spectrum(ion spray): m/z=380 (M+1); ¹HNMR (CDCl₃): 8.59 (s, 1H), 8.15 (d, 1H),7.38 (d, 1H), 6.99 (s, 1H), 6.95 (d, 1H), 6.94 (d, 1H), 5.89 (br. s,2H), 4.24 (t, 1H), 3.01 (m, 1H), 2.82 (m, 1H), 2.75 (t, 2H), 2.45 (m,1H), 1.88 (m, 1H), 1.74-1.62 (m, 5H), 1.43 (m, 2H), 1.38-1.13 (m, 4H),0.93 (m, 2H).

Example 17 6-(3,3-Dimethyl-1-phenethylamino-indan-5-yloxy)-nicotinamide

Using a method similar to Example 14, using6-(3,3-dimethyl-1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 11, 100mg, 0.337 mmol), phenethylamine (49 mg, 0.405 mmol), Ti(^(i)PrO)₄ (192mg, 0.675 mmol), TiCl₄ (1.0M/DCM, 0.675 ml, 0.675 mmol), and NaBH₃CN (42mg, 0.675 mmol) gives the title compound (90 mg) as a white solid. Massspectrum (ion spray): m/z=402 (M+1); ¹HNMR (CDCl₃): 8.60 (s, 1H), 8.14(d, 1H), 7.32-7.19 (m, 6H), 6.95-6.88 (m, 3H), 6.25 (br. s, 2H), 4.31(t, 1H), 3.02 (m, 2H), 2.86 (m, 2H), 2.33 (m, 1H), 1.68 (m, 3H), 1.31(s, 3H), 1.17 (s, 3H).

Example 18 6-(1-Phenethylamino-indan-5-yloxy)-nicotinamide

Using a method similar to Example 14, using6-(1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 4, 805 mg, 3.00mmol), phenethylamine (436 mg, 3.60 mmol), Ti(^(i)PrO)₄ (1.70 g, 6.00mmol), TiCl₄ (1.0M/DCM, 6.00 ml, 6.00 mmol), and NaBH₃CN (377 mg, 6.00mmol) gives the title compound (984 mg) as a light yellow solid. Massspectrum (ion spray): m/z=374 (M+1); ¹HNMR (CDCl₃): 8.59 (s, 1H), 8.15(d, 1H), 7.33-7.19 (m, 6H), 6.98 (s, 1H), 6.95-6.91 (m, 21H, 5.99 (br.s, 2H), 4.26 (t, H), 3.04-2.94 (m, 3H), 2.88-2.74 (m, 3H), 2.44 (m, 1H),1.84 (m, 1H).

Example 19 6-(4-Methyl-1-phenethylamino-indan-5-yloxy)-nicotinamide

Using a method similar to Example 14, using6-(4-methyl-1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 12, 100 mg,0.354 mmol), phenethylamine (52 mg, 0.425 mmol), Ti(^(i)PrO)₄ (201 mg,0.708 mmol), TiCl₄ (11.0M/DCM, 0.708 ml, 0.708 mmol), and NaBH₃CN (44mg, 0.708 mmol) gives the title compound (112 mg) as a white solid. Massspectrum (ion spray): m/z=388 (M+1); ¹HNMR (CDCl₃): 8.57 (s, 1H), 8.14(d, 1H), 7.32-7.19 (m, 5H), 7.14 (d, 1H), 6.91-6.87 (m, 2H), 6.03 (br.s, 2H), 428 (t, 1H), 3.01 (t, 2H), 2.94 (m, 1H), 2.85 (m, 2H), 2.74 (m,1H), 2.44 (m, 1H), 2.02 (s, 3H), 1.86 (m, 1H).

Example 206-{1-[Methyl-(3-methyl-butyl)-amino)]-indan-5-yloxy}-nicotinamide

Heat a suspension of 6-(1-oxo-indan-5-yloxy)-nicotinamide (Intermediate4, 268 mg, 1.00 mmol), methyl isoamylamine (121 mg, 1.20 mmol),Ti(^(i)PrO)₄ (426 mg, 1.50 mmol), and THF (0.5 ml) at 50° C. overnightDilute the mixture with MeOH (5 ml), add NaBH₃CN (94 mg, 1.50 mmol), andstir at ambient temperature for 16 hours. Quench reaction with 2N aq.NaOH (10 ml) and stir for ca. one hour. Remove solids via filtration andwash filtercake with EtOAc. Separate layers in the filtrate/wash andwash organic layer with brine before drying (MgSO₄) and concentrating.Redissolve the filtrate in 5% AcOH/MeOH and purify on cation exchangeresin (2 g, Varian). Further purify product on reverse-phase HPLC(C18column, 10% ACN/water (0.01% TFA buffer) to 95% ACN/water over 15minutes) and free-base with 1M aq. K₂CO₃ I EtOAc to give the titlecompound (151 mg) as a white solid. Mass spectrum (ion spray): m/z=354(M+1); ¹HNMR (CDCl₃): 8.60 (s, 1H), 8.15 (d, 1H), 7.37 (d, 1H),6.98-6.92 (m, 3H), 6.09 (br. s, 2H), 4.42 (t, 1H), 2.87 (m, 2H), 2.43(m, 2H), 2.20 (s, 3H), 2.08 (m, 2H), 1.61 (m, 1H), 1.41 (m 2H), 0.88 (d,6H).

Example 21 6-[1-(Methyl-phenethyl-amino)-indan-5-yloxy]-nicotinamide

Using a method similar to Example 13, using6-(1-phenethylamino-indan-5-yloxy)-nicotinamide (example 18, 980 mg,2.62 mmol), paraformaldehyde (1.03 g), and NaBH₃CN (494 mg, 7.87 mmol)gives the title compound (930 mg) as a light yellow solid. Mass spectrum(ion spray): m/z=388 (M+1); ¹HNMR (CDCl₃): 8.59 (s, 1H), 8.16 (d, 1H),7.30-7.17 (m, 6H), 6.97-6.91 (m, 3H), 5.79 (br. s, 2H), 4.45 (t, 1H),2.96-2.74 (m, 4H), 2.68 (m, 2H), 2.33 (s, 3H), 2.09 (m, 2H).

Examples 22-200

General Mass Example IUPAC name Procedure Intermed. # Reagent (pos. ion)22 6-(8-Pentylamino-5,6,7,8- II 1 n-pentylamine 354tetrahydro-naphthalen-2- yloxy)-nicotinamide 236-(5-Pentylamino-5,6,7,8- II 2 n-pentylamine 354tetrahydro-naphthalen-2- yloxy)-nicotinamide 246-(5-Pentylamino-5,6,7,8- II 3 n-pentylamine 354tetrahydro-naphthalen-1- yloxy)-nicotinamide 256-(1-Pentylamino-indan-5- II 4 n-pentylamine 340 yloxy)-nicotinamide 266-(1-Pentylamino-indan-4- II 5 n-pentylamine 340 yloxy)-nicotinamide 276-(8-Benzylamino-5,6,7,8- II 1 benzylamine 374 tetrahydro-naphthalen-2-yloxy)-nicotinamide 28 6-(5-Benzylamino-5,6,7,8- II 2 benzylamine 374tetrahydro-naphthalen-2- yloxy)-nicotinamide 296-(5-Benzylamino-5,6,7,8- II 3 benzylamine 374 tetrahydro-naphthalen-1-yloxy)-nicotinamide 30 6-(1-Benzylamino-indan-4- II 5 benzylamine 360yloxy)-nicotinamide 31 6-(8-Phenethylamino-5,6,7,8- II 1 phenethylamine388 tetrahydro-naphthalen-2- yloxy)-nicotinamide 326-(5-Phenethylamino-5,6,7,8- II 2 phenethylamine 388tetrahydro-naphthalen-2- yloxy)-nicotinamide 336-(5-Phenethylamino-5,6,7,8- II 3 phenethylamine 388tetrahydro-naphthalen-1- yloxy)-nicotinamide 346-(1-Phenethylamino-indan-4- II 5 phenethylamine 374 yloxy)-nicotinamide35 6-{8-[2-(3-Fluoro-phenyl)- II 1 3-fluorophenethylamine 406ethylamino]-5,6,7,8- tetrahydro-naphthalen-2- yloxy}-nicotinamide 366-{5-[2-(3-Fluoro-phenyl)- II 2 3-fluorophenethylamine 406ethylamino]-5,6,7,8- tetrahydro-naphthalen-2- yloxy}-nicotinamide 376-{5-[2-(3-Fluoro-phenyl)- II 3 3-fluorophenethylamine 406ethylamino]-5,6,7,8- tetrahydro-naphthalen-1- yloxy}-nicotinamide 386-{3-[2-(3-Fluoro-phenyl)- II 6 3-fluorophenethylamine 392ethylamino]-indan-5-yloxy}- nicotinamide 39 6-{1-[2-(3-Fluoro-phenyl)-II 4 3-fluorophenethylamine 392 ethylamino]-indan-5-yloxy}- nicotinamide40 6-{1-[2-(3-Fluoro-phenyl)- II 5 3-fluorophenethylamine 392ethylamino]-indan-4-yloxy}- nicotinamide 41 6-[8-(3-Methyl-butylamino)-II 1 isoamylamine 354 5,6,7,8-tetrahydro- naphthalen-2-yloxy]-nicotinamide 42 6-[5-(3-Methyl-butylamino)- II 2 isoamylamine 3545,6,7,8-tetrahydro- naphthalen-2-yloxy]- nicotinamide 436-[5-(3-Methyl-butylamino)- II 3 isoamylamine 354 5,6,7,8-tetrahydro-naphthalen-1-yloxy]- nicotinamide 44 6-[8-(4-Methyl- II 1 4- 380cyclohexylamino)-5,6,7,8- methylcyclohexylamine,tetrahydro-naphthalen-2- cis/trans mixture yloxy]-nicotinamide 456-[5-(4-Methyl- II 2 4- 380 cyclohexylamino)-5,6,7,8-methylcyclohexylamine, tetrahydro-naphthalen-2- cis/trans mixtureyloxy]-nicotinamide 46 6-[5-(4-Methyl- II 3 4- 380cyclohexylamino)-5,6,7,8- methylcyclohexylamine,tetrahydro-naphthalen-1- cis/trans mixture yloxy]-nicotinamide 476-[1-(4-Methyl- II 4 4- 366 cyclohexylamino)-indan-5-methylcyclohexylamine, yloxy]-nicotinamide cis/trans mixture 486-[1-(4-Methyl- II 5 4- 366 cyclohexylamino)-indan-4-methylcyclohexylamine, yloxy]-nicotinamide cis/trans mixture 496-(7-Pentylamino-5,6,7,8- II 7 n-pentylamine 354tetrahydro-naphthalen-2- yloxy)-nicotinamide 506-(6-Pentylamino-5,6,7,8- II 8 n-pentylamine 354tetrahydro-naphthalen-2- yloxy)-nicotinamide 516-(6-Pentylamino-5,6,7,8- II 9 n-pentylamine 354tetrahydro-naphthalen-1- yloxy)-nicotinamide 526-(7-Pentylamino-5,6,7,8- II 10 n-pentylamine 354tetrahydro-naphthalen-1- yloxy)-nicotinamide 536-(7-Benzylamino-5,6,7,8- II 7 benzylamine 374 tetrahydro-naphthalen-2-yloxy)-nicotinamide 54 6-(6-Benzylamino-5,6,7,8- II 8 benzylamine 374tetrahydro-naphthalen-2- yloxy)-nicotinamide 556-(6-Benzylamino-5,6,7,8- II 9 benzylamine 374 tetrahydro-naphthalen-1-yloxy)-nicotinamide 56 6-(7-Benzylamino-5,6,7,8- II 10 benzylamine 374tetrahydro-naphthalen-1- yloxy)-nicotinamide 576-(7-Phenethylamino-5,6,7,8- II 7 phenethylamine 387tetrahydro-naphthalen-2- yloxy)-nicotinamide 586-(6-Phenethylamino-5,6,7,8- II 8 phenethylamine 387tetrahydro-naphthalen-2- yloxy)-nicotinamide 596-(6-Phenethylamino-5,6,7,8- II 9 phenethylamine 387tetrahydro-naphthalen-1- yloxy)-nicotinamide 606-(7-Phenethylamino-5,6,7,8- II 10 phenethylamine 387tetrahydro-naphthalen-1- yloxy)-nicotinamide 616-{7-[2-(3-Fluoro-phenyl)- II 7 3-fluorophenethylamine 406ethylamino]-5,6,7,8- tetrahydro-naphthalen-2- yloxy}-nicotinamide 626-{6-[2-(3-Fluoro-phenyl)- II 8 3-fluorophenethylamine 406ethylamino]-5,6,7,8- tetrahydro-naphthalen-2- yloxy}-nicotinamide 636-{6-[2-(3-Fluoro-phenyl)- II 9 3-fluorophenethylamine 406ethylamino]-5,6,7,8- tetrahydro-naphthalen-1- yloxy}-nicotinamide 646-{7-[2-(3-Fluoro-phenyl)- II 10 3-fluorophenethylamine 406ethylamino]-5,6,7,8- tetrahydro-naphthalen-1- yloxy}-nicotinamide 656-[7-(3-Methyl-butylamino)- II 7 isoamylamine 354 5,6,7,8-tetrahydro-naphthalen-2-yloxy]- nicotinamide 66 6-[6-(3-Methyl-butylamino)- II 8isoamylamine 354 5,6,7,8-tetrahydro- naphthalen-2-yloxy]- nicotinamide67 6-[6-(3-Methyl-butylamino)- II 9 isoamylamine 354 5,6,7,8-tetrahydro-naphthalen-1-yloxy]- nicotinamide 68 6-[7-(3-Methyl-butylamino)- II 10isoamylamine 354 5,6,7,8-tetrahydro- naphthalen-1-yloxy]- nicotinamide69 6-[7-(4-Methyl- II 7 4- 380 cyclohexylamino)-5,6,7,8-methylcyclohexylamine, tetrahydro-naphthalen-2- cis/trans mixtureyloxy]-nicotinamide 70 6-[6-(4-Methyl- II 9 4- 380cyclohexylamino)-5,6,7,8- methylcyclohexylamine,tetrahydro-naphthalen-1- cis/trans mixture yloxy]-nicotinamide 716-[7-(4-Methyl- II 10 4- 380 cyclohexylamino)-5,6,7,8-methylcyclohexylamine, tetrahydro-naphthalen-1- cis/trans mixtureyloxy]-nicotinamide 72 6-[7-(3-Phenyl-propylamino)- II 73-phenylpropylamine 402 5,6,7,8-tetrahydro- naphthalen-2-yloxy]-nicotinamide 73 6-[6-(3-Phenyl-propylamino)- II 8 3-phenylpropylamine402 5,6,7,8-tetrahydro- naphthalen-2-yloxy]- nicotinamide 746-[6-(3-Phenyl-propylamino)- II 9 3-phenylpropylamine 4025,6,7,8-tetrahydro- naphthalen-1-yloxy]- nicotinamide 756-[7-(3-Phenyl-propylamino)- II 10 3-phenylpropylamine 4025,6,7,8-tetrahydro- naphthalen-1-yloxy]- nicotinamide 766-[5-(2-Methylsulfanyl- II 2 2-(methylthio)- 358 ethylamino)-5,6,7,8-ethylamine tetrahydro-naphthalen-2- yloxy]-nicotinamide 776-[1-(2-Methylsulfanyl- II 4 2-(methylthio)- 344ethylamino)-indan-5-yloxy]- ethylamine nicotinamide 786-{5-[2-(3-Methoxy-phenyl)- II 2 3- 418 ethylamino]-5,6,7,8-methoxylphenethylamine tetrahydro-naphthalen-2- yloxy}-nicotinamide 796-{1-[2-(3-Methoxy-phenyl)- II 4 3- 404 ethylamino]-indan-5-yloxy}-methoxylphenethylamine nicotinamide 80 6-[5-(2-Dimethylamino- II 2 N,N-356 ethylamino)-5,6,7,8- dimethylaminoethylaminetetrahydro-naphthalen-2- yloxy]-nicotinamide 81 6-[1-(2-Dimethylamino-II 4 N,N- 341 ethylamino)-indan-5-yloxy]- dimethylaminoethylaminenicotinamide 82 6-[5-(2-Pyrrolidin-1-yl- II 2 2-pyrrolidinoethylamine381 ethylamino)-5,6,7,8- tetrahydro-naphthalen-2- yloxy]-nicotinamide 836-[1-(2-Pyrrolidin-1-yl- II 4 2-pyrrolidinoethylamine 367ethylamino)-indan-5-yloxy]- nicotinamide 84 6-[5-(2-Pyridin-2-yl- II 22-(2- 389 ethylamino)-5,6,7,8- aminoethyl)pyridinetetrahydro-naphthalen-2- yloxy]-nicotinamide 85 6-[1-(2-Pyridin-2-yl- II4 2-(2- 375 ethylamino)-indan-5-yloxy]- aminoethyl)pyridine nicotinamide86 6-[5-(2-Morpholin-4-yl- II 2 4-(2-aminoethyl)- 397ethylamino)-5,6,7,8- morpholine tetrahydro-naphthalen-2-yloxy]-nicotinamide 87 6-[1-(2-Morpholin-4-yl- II 4 4-(2-aminoethyl)-383 ethylamino)-indan-5-yloxy]- morpholine nicotinamide 886-[1-(1,2-Diphenyl- II 4 1,2-diphenylethylamine 450ethylamino)-indan-5-yloxy]- nicotinamide 89 6-{5-[2-(4-Fluoro-phenyl)-II 2 4-fluoro- 406 ethylamino]-5,6,7,8- phenethylaminetetrahydro-naphthalen-2- yloxy}-nicotinamide 906-{1-[2-(4-Fluoro-phenyl)- II 4 4-fluoro- 390ethylamino]-indan-5-yloxy}- phenethylamine nicotinamide 916-[5-(2-Acetylamino- II 2 N-acetyl- 369 ethylamino)-5,6,7,8-ethylenediamine tetrahydro-naphthalen-2- yloxy]-nicotinamide 926-[1-(2-Acetylamino- II 4 N-acetyl- 355 ethylamino)-indan-5-yloxy]-ethylenediamine nicotinamide 93 6-{5-[2-(5-Fluoro-1H-indol-3- II 25-fluorotryptamine 445 yl)-ethylamino]-5,6,7,8- tetrahydro-naphthalen-2-yloxy}-nicotinamide 94 6-{1-[2-(5-Fluoro-1H-indol-3- II 45-fluorotryptamine 431 yl)-ethylamino]-indan-5- yloxy}-nicotinamide 953-[6-(5-Carbamoyl-pyridin-2- II 2 4-Amino-butyric acid 398yloxy)-1,2,3,4-tetrahydro- isopropyl ester naphthalen-1-ylamino]-propionic acid isopropyl ester 96 3-[5-(5-Carbamoyl-pyridin-2- II 44-Amino-butyric acid 384 yloxy)-indan-1-ylamino]- isopropyl esterpropionic acid isopropyl ester 97 6-(2-Pentylamino-indan-5- I 15n-pentylamine 340 yloxy)-nicotinamide 98 6-(2-Pentylamino-indan-4- I 16n-pentylamine 340 yloxy)-nicotinamide 99 6-(2-Benzylamino-indan-5- I 15benzylamine 360 yloxy)-nicotinamide 100 6-(2-Benzylamino-indan-4- I 16benzylamine 360 yloxy)-nicotinamide 101 6-[2-(3-Phenyl-propylamino)- I15 3-phenylpropylamine 388 indan-5-yloxy]-nicotinamide 1026-[2-(3-Phenyl-propylamino)- I 16 3-phenylpropylamine 388indan-4-yloxy]-nicotinamide 103 6-[2-(3-Methyl-butylamino)- I 15isoamylamine 340 indan-5-yloxy]-nicotinamide 1046-[2-(3-Methyl-butylamino)- I 16 isoamylamine 340indan-4-yloxy]-nicotinamide 105 6-[2-(2-Phenyl-propylamino)- I 152-phenylpropylamine 388 indan-5-yloxy]-nicotinamide 1066-[2-(2-Phenyl-propylamino)- I 16 2-phenylpropylamine 388indan-4-yloxy]-nicotinamide 107 6-(2-Phenethylamino-indan-5- I 15phenethylamine 374 yloxy)-nicotinamide 108 6-(2-Phenethylamino-indan-4-I 16 phenethylamine 374 yloxy)-nicotinamide 1096-{2-[(5-Fluoro-1H-indol-3- I 15 5-fluorotryptamine 417ylmethyl)-amino]-indan-5- yloxy}-nicotinamide 1106-{2-[(5-Fluoro-1H-indol-3- I 16 5-fluorotryptamine 417ylmethyl)-amino]-indan-4- yloxy}-nicotinamide 1116-[2-(3-Dimethylamino-2,2- I 15 N,N,2,2-tetramethyl- 382dimethyl-propylamino)-indan- 1,3-propane-diamine 5-yloxy]-nicotinamide112 6-[2-(3-Dimethylamino-2,2- I 16 N,N,2,2-tetramethyl- 382dimethyl-propylamino)-indan- 1,3-propane-diamine 4-yloxy]-nicotinamide113 6-{5-[(Benzo[b]thiophen-3- II 2 1-benzothiophen-3- 430ylmethyl)-amino]-5,6,7,8- ylmethylamine tetrahydro-naphthalen-2-yloxy}-nicotinamide 114 6-{1-[(Benzo[b]thiophen-3- II 41-benzothiophen-3- 416 ylmethyl)-amino]-indan-5- ylmethylamineyloxy}-nicotinamide 115 6-[5-(2-Methoxy-ethylamino)- II 22-methoxyethylamine 342 5,6,7,8-tetrahydro- naphthalen-2-yloxy]-nicotinamide 116 6-[1-(2-Methoxy-ethylamino)- II 4 2-methoxyethylamine328 indan-5-yloxy]-nicotinamide 117 6-{5-[2-(3-Trifluoromethyl- II 23-(trifluoromethyl)- 456 phenyl)-ethylamino]-5,6,7,8- phenethylaminetetrahydro-naphthalen-2- yloxy}-nicotinamide 1186-{1-[2-(3-Trifluoromethyl- II 4 3-(trifluoromethyl)- 442phenyl)-ethylamino]-indan-5- phenethylamine yloxy}-nicotinamide 1196-[5-(2-m-Tolyl-ethylamino)- II 2 3-methyl- 402 5,6,7,8-tetrahydro-phenethylamine naphthalen-2-yloxy]- nicotinamide 1206-{5-[2-(4-Fluoro-phenyl)-1,1- II 2 1,1-dimethyl-2-(4- 299dimethyl-ethylamino]-5,6,7,8- fluorophenyl)- tetrahydro-naphthalen-2-ethylamine yloxy}-nicotinamide 121 6-{1-[2-(4-Fluoro-phenyl)-1,1- II 41,1-dimethyl-2-(4- 285 dimethyl-ethylamino]-indan-5- fluorophenyl)-yloxy}-nicotinamide ethylamine 122 6-[5-(3-Hydroxy- II 23-hydroxypropylamine 343 propylamino)-5,6,7,8- tetrahydro-naphthalen-2-yloxy]-nicotinamide 123 6-[1-(3-Hydroxy- II 4 3-hydroxypropylamine 329propylamino)-indan-5-yloxy]- nicotinamide 124 6-[5-(2,2,2-Trifluoro- II2 2,2,2- 299 ethylamino)-5,6,7,8- trifluoroethylaminetetrahydro-naphthalen-2- yloxy]-nicotinamide 125 6-[1-(2,2,2-Trifluoro-II 4 2,2,2- 285 ethylamino)-indan-5-yloxy]- trifluoroethylaminenicotinamide 126 6-[5-(2,2-Diphenyl- II 2 2,2-diphenylethylarmine 464ethylamino)-5,6,7,8- tetrahydro-naphthalen-2- yloxy]-nicotinamide 1276-[5-(4-Phenyl-piperidin-1-yl)- III 13 4-phenylpiperidine 4285,6,7,8-tetrahydro- naphthalen-2-yloxy]- nicotinamide 1286-[1-(4-Phenyl-piperidin-1-yl)- III 14 4-phenylpiperidine 414indan-5-yloxy]-nicotinamide 129 6-[5-(Benzyl-methyl-amino)- III 13N-methylbenzylamine 388 5,6,7,8-tetrahydro- naphthalen-2-yloxy]-nicotinamide 130 6-[1-(Benzyl-methyl-amino)- III 14 N-methylbenzylamine374 indan-5-yloxy]-nicotinamide 131 6-[5-(3,4-Dihydro-1H- III 131,2,3,4-tetrahydro- 400 isoquinolin-2-yl)-5,6,7,8- isoquinolinetetrahydro-naphthalen-2- yloxy]-nicotinamide 132 6-[1-(3,4-Dihydro-1H-III 14 1,2,3,4-tetrahydro- 386 isoquinolin-2-yl)-indan-5- isoquinolineyloxy]-nicotinamide 133 6-(5-Thiomorpholin-4-yl- III 13 thio-morpholine370 5,6,7,8-tetrahydro- naphthalen-2-yloxy)- nicotinamide 1346-(1-Thiomorpholin-4-yl- III 14 thio-morpholine 356indan-5-yloxy)-nicotinamide 135 2-[6-(5-Carbamoyl-pyridin-2- III 131,2,3,4-tetrahydro- 499 yloxy)-1,2,3,4-tetrahydro- isoquinoline-3-naphthalen-1-yl]-1,2,3,4- carboxylic acid tert-tetrahydro-isoquinoline-3- butylamide carboxylic acid tert- butylamide136 2-[6-(5-Carbamoyl-pyridin-2- III 13 1,2,3,4-tetrahydro- 499yloxy)-1,2,3,4-tetrahydro- isoquinoline-3- naphthalen-1-yl]-1,2,3,4-carboxylic acid tert- tetrahydro-isoquinoline-3- butylamide carboxylicacid tert- butylamide 137 6-[5-(5-Oxo-[1,4]diazepan-1- III 132,3,6,7-tetrahydro-(1H)- 381 yl)-5,6,7,8-tetrahydro-1,4-diazepin-5(4H)-one naphthalen-2-yloxy]- nicotinamide 1386-[1-(5-Oxo-[1,4]diazepan-1- III 14 2,3,6,7-tetrahydro-(1H)- 367yl)-indan-5-yloxy]- 1,4-diazepin-5(4H)-one nicotinamide 1396-[5-(Methyl-phenethyl- III 13 N-methyl- 402 amino)-5,6,7,8-tetrahydro-phenethylamine naphthalen-2-yloxy]- nicotinamide 1406-[1-(3-Acetylamino- III 14 3-acetamido-pyrrolidine 381pyrrolidin-1-yl)-indan-5-yloxy]- nicotinamide 1416-[1-(3-Phenyl-piperidin-1-yl)- III 14 3-phenylpiperidine 414indan-5-yloxy]-nicotinamide 142 6-[1-(3-Phenyl-pyrrolidin-1-yl)- III 143-phenylpyrrolidine 400 indan-5-yloxy]-nicotinamide 1436-[1-(3-Propylamino- II 4 N-propyl-1,3- 369 propylamino)-indan-5-yloxy]-propanediamine nicotinamide 144 6-[1-(3,3-Dimethyl- II 4 3,3-dimethyl,-354 butylamino)-indan-5-yloxy]- butylamine nicotinamide 1456-(1-Decylamino-indan-5- II 4 n-decylamine 410 yloxy)-nicotinamide 1466-[1-(2-Ethyl-hexylamino)- II 4 2-ethyl-hexylamine 382indan-5-yloxy]-nicotinamide 147 6-{1-[(Tetrahydro-furan-2- II 4tetrahydro-furfurylamine 354 ylmethyl)-amino]-indan-5-yloxy}-nicotinamide 148 6-(1-Cycloheptylamino-indan- II 4cycloheptylamine 366 5-yloxy)-nicotinamide 1496-{1-[2-(1-Methyl-pyrrolidin-2- II 4 2-(2-aminoethyl)-1- 381yl)-ethylamino]-indan-5- methylpyrrolidine yloxy}-nicotinamide 1506-(1-Cyclopropylamino-indan- II 4 cyclopropylamine 3105-yloxy)-nicotinamide 151 6-[1-(1,3-Dimethyl- II 41,3-dimethyl-butylamine 354 butylamino)-indan-5-yloxy]- nicotinamide 1526-(1-Cyclooctylamino-indan- II 4 cyclooctylamine 3805-yloxy)-nicotinamide 153 6-[1-(2,3-Dimethyl- II 4 2,3- 380cyclohexylamino)-indan-5- dimethylcyclohexylamine, yloxy]-nicotinamidecis/trans mixture 154 6-(1-Cyclobutylamino-indan- II 4 cyclobutylamine324 5-yloxy)-nicotinamide 155 6-(1-Cyclopentylamino-indan- II 4cyclopentylamine 338 5-yloxy)-nicotinamide 156 6-[1-(Cyclohexylmethyl-II 4 aminomethyl- 366 amino)-indan-5-yloxy]- cyclohexane nicotinamide157 6-{1-[(1-Ethyl-pyrrolidin-2- II 4 2-aminomethyl-1- 381ylmethyl)-amino]-indan-5- ethylpyrrolidine yloxy}-nicotinamide 1586-[1-(3-Cyclohexylamino- II 4 3-Cyclohexylamino- 409propylamino)-indan-5-yloxy]- propylamine nicotinamide 1596-[1-(3-Methyl- II 4 3-methyl- 366 cyclohexylamino)-indan-5-cyclohexylamine yloxy]-nicotinamide 160 6-(1-Cyclohexylamino-indan- II 4cyclohexylamine 350 5-yloxy)-nicotinamide 1616-[1-(1-Isopropyl-2-methyl- II 4 3-amino-2,4-dimethyl- 366propylamino)-indan-5-yloxy]- pentane nicotinamide 1626-[1-(2-Cyclohex-1-enyl- II 4 2-(1-cyclohexenyl)- 378ethylamino)-indan-5-yloxy]- ethylamine nicotinamide 1636-[1-(2-Methyl-butylamino)- II 4 2-methylbutylamine 340indan-5-yloxy]-nicotinamide 164 6-[1-(4-Hydroxy- II 4 trans-4-Hydroxy-368 cyclohexylamino)-indan-5- cyclohexylamine yloxy]-nicotinamide 1656-[1-(1,4-Dimethyl- II 4 2,4- 368 pentylamino)-indan-5-yloxy]-dimethylpentylamine nicotinamide 166 6-[1-(1-Cyclohexyl- II 41-Cyclohexyl- 380 ethylamino)-indan-5-yloxy]- ethylamine nicotinamide167 6-[1-(3,3,5-Trimethyl- II 4 3,3,5-Trimethyl- 394cyclohexylamino)-indan-5- cyclohexylamine yloxy]-nicotinamide 1686-[1-(2-Carbamoyl- II 4 2-amino-cyclohexane- 395cyclohexylamino)-indan-5- carboxamide yloxy]-nicotinamide 1696-[1-(Cyclopropylmethyl- II 4 cyclopropyl- 324 amino)-indan-5-yloxy]-methylamine nicotinamide 170 6-[1-(3-Butoxy-propylamino)- II 43-butoxypropylamine 384 indan-5-yloxy]-nicotinamide 1716-[1-(2,2,3,3,4,4,4- II 4 2,2,3,3,4,4,4- 450 Heptafluoro-butylamino)-Heptafluoro-butylamine indan-5-yloxy]-nicotinamide 1726-{1-[3-(2-Oxo-pyrrolidin-1-yl)- II 4 1-(2-Amino-ethyl)- 395propylamino]-indan-5-yloxy}- pyrrolidin-2-one nicotinamide 1736-[1-(3-Azepan-1-yl- II 4 3-hexamethyleneimino- 409propylamino)-indan-5-yloxy]- 1-propylamine nicotinamide 1746-[1-(2,2,3,3,3-Pentafluoro- II 4 2,2,3,3,3-Pentafluoro- 402propylamino)-indan-5-yloxy]- propylamine nicotinamide 1756-{1-[(2-Hydroxy- II 4 cis-2-aminomethyl- 410 cyclooctylmethyl)-amino]-cyclooctanol indan-5-yloxy}-nicotinamide 1766-[1-(Bicyclohexyl-2-ylamino)- II 4 2-aminobicyclohexyl 434indan-5-yloxy]-nicotinamide 177 6-[1-(2-Hydroxy- II 4 2-hydroxy- 368cyclohexylamino)-indan-5- cyclohexylamine yloxy]-nicotinamide 1786-{1-[2-(2-Methyl-cyclohexyl)- II 4 2-(2-Methyl- 394ethylamino]-indan-5-yloxy}- cyclohexyl)-ethylamine nicotinamide 1796-{1-[2-(4-Methyl-cyclohexyl)- II 4 2-(4-methylcyclohexyl)- 394ethylamino]-indan-5-yloxy}- ethylamine nicotinamide 1806-[1-(2-Cyclopentyl- II 4 2-cyclopentyl- 366 ethylamino)-indan-5-yloxy]-ethylamine nicotinamide 181 6-[1-(Phenethylamino- I 17 phenethylamine388 methyl)-indan-5-yloxy]- nicotinamide 182 6-[8-(Phenethylamino- I 19phenethylamine 402 methyl)-5,6,7,8-tetrahydro- naphthalen-2-yloxy]-nicotinamide 183 6-[3-(Phenethylamino- I 18 phenethylamine 388methyl)-indan-5-yloxy]- nicotinamide 184 6-[5-(Phenethylamino- I 20phenethylamine 402 methyl)-5,6,7,8-tetrahydro- naphthalen-1-yloxy]-nicotinamide 185 6-[1-(Benzylamino-methyl)- I 17 benzylamine 374indan-5-yloxy]-nicotinamide 186 6-[8-(Benzylamino-methyl)- I 19benzylamine 388 5,6,7,8-tetrahydro- naphthalen-2-yloxy]- nicotinamide187 6-[3-(Benzylamino-methyl)- I 18 benzylamine 374indan-5-yloxy]-nicotinamide 188 6-[5-(Benzylamino-methyl)- I 20benzylamine 388 5,6,7,8-tetrahydro- naphthalen-1-yloxy]- nicotinamide189 6-{1-[(3-Methyl-butylamino)- I 17 isoamylamine 354methyl]-indan-5-yloxy}- nicotinamide 190 6-{8-[(3-Methyl-butylamino)- I19 isoamylamine 368 methyl]-5,6,7,8-tetrahydro- naphthalen-2-yloxy}-nicotinamide 191 6-{3-[(3-Methyl-butylamino)- I 18 isoamylamine 354methyl]-indan-5-yloxy}- nicotinamide 192 6-{5-[(3-Methyl-butylamino)- I20 isoamylamine 368 methyl]-5,6,7,8-tetrahydro- naphthalen-1-yloxy}-nicotinamide 193 6-{1-[(2-Cyclohexyl- I 17 2-cyclohexyl- 394ethylamino)-methyl]-indan-5- ethylamine yloxy}-nicotinamide 1946-{8-[(2-Cyclohexyl- I 19 2-cyclohexyl- 408 ethylamino)-methyl]-5,6,7,8-ethylamine tetrahydro-naphthalen-2- yloxy}-nicotinamide 1956-{5-[(2-Cyclohexyl- I 20 2-cyclohexyl- 408 ethylamino)-methyl]-5,6,7,8-ethylamine tetrahydro-naphthalen-1- yloxy}-nicotinamide 1966-{1-[(Cyclohexylmethyl- I 17 aminomethyl- 380 amino)-methyl]-indan-5-cyclohexane yloxy}-nicotinamide 197 6-{8-[(Cyclohexylmethyl- I 19aminomethyl- 394 amino)-methyl]-5,6,7,8- cyclohexanetetrahydro-naphthalen-2- yloxy}-nicotinamide 1986-{3-[(Cyclohexylmethyl- I 18 aminomethyl- 380 amino)-methyl]-indan-5-cyclohexane yloxy}-nicotinamide 199 6-{5-[(Cyclohexylmethyl- I 20aminomethyl- 394 amino)-methyl]-5,6,7,8- cyclohexanetetrahydro-naphthalen-1- yloxy}-nicotinamide 200 6-{1-[(2-Cyclopentyl- I17 2-cyclopentyl- 380 ethylamino)-methyl]-indan-5- ethylamineyloxy}-nicotinamide

Example 2016-{5-[(3-Methyl-butylamino)-methyl]-5,6,7,8-tetrahydro-naphthalen-2-yloxy}-nicotinamide

2116496:

Add isovaleraldehyde (64.5 mg, 0.750 mmol) to a solution of6-(5-aminomethyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide(intermediate 21, 148 mg, 0.500 mmol) dissolved in MeOH (5 mL) and stirat ambient temperature for 1.5 hours before adding NaBH₄ (38 mg, 1.00mmol). After stirring for an additional two hours, concentrate thereaction mixture and redissolved in EtOAc. Wash the EtOAc solution with5% aq. KOH and brine before drying (MgSO₄) and concentrating. Purify onsilica gel (5% (1N NH₃/MeOH)/DCM) to obtain 123 mg of the title compoundas a white foam. Mass spectrum (ion spray): m/z=368 (M+1); ¹HNMR(CDCl₃): 8.59 (s, 1H), 8.15 (d, 1H), 7.25 (d, 1H), 6.94 (d, 1H), 6.89(d, 1H), 6.85 (s, 1H), 5.82 (br. s, 2H), 2.97 (m, 1H), 2.84 (m, 2H),2.76 (m, 2H), 2.66 (m, 2H), 1.85 (m, 3H), 1.74 (m 1H), 1.62 (m, 1H),1.41 (m, 2H), 0.90 (d, 6H).

Example 2026-{5-[(3,3-Dimethyl-butylamino)-methyl]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-nicotinamide

Using a method similar to Example 201, using6-(5-aminomethyl-5,6,7,8-tetrahydro-naphtalene-1-yloxy)-nicotinamide(intermediate 20, 148 mg, 0.500 mmol), 3,3-dimethylbutyraldehyde (75 mg,0.750 mmol), and NaBH₄ (38 mg, 1.00 mmol) gives the title compound (130mg) as a white foam. Mass spectrum (ion spray): m/z=382 (M+1); ¹HNMR(CDCl₃): 8.55 (s, 1H), 8.14 (d, 1H), 7.22-7.14 (m, 2H), 6.90 (m, 2H),5.76 (br. s, 2H), 3.03 (m, 1H), 2.92-2.80 (m, 2H), 2.71-2.55 (m, 3H),2.49-2.41 (m, 1H), 1.85-1.65 (m, 4H), 1.42 (t, 2H), 0.90 (s, 9H).

Example 2036-(5-Hexylaminomethyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide

Using a method similar to Example 201, using6-(5-aminomethyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide(intermediate 20, 148 mg, 0.500 mmol), hexanal (75 mg, 0.750 mmol), andNaBH₄ (38 mg, 1.00 mmol) gives the title compound (110 mg) as acolorless glass. Mass spectrum (ion spray): m/z=382 (M+1); ¹HNMR(CDCl₃): 8.57 (s, 1H), 8.15 (d, 1H), 7.21-7.14 (m, 2H), 6.90 (m, 2H),6.05 (br. s, 2H), 3.01 (m, 1H), 2.90-2.79 (m, 2H), 2.69-2.55 (m, 3H),2.50-2.42 (m, 1H), 1.84-1.64 (m, 4H), 1.49 (m, 2H), 1.29 (m, 6H), 0.89(t, 3H).

Example 2046-(5-Cyclohexylaminomethyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide

Add NaBH₃CN (63 mg, 1.00 mmol) to a solution of6-(5-aminomethyl-5,6,7,8-tetrahydro naphthalen-1-yloxy)-nicotinamide(intermediate 20, 148 mg, 0.500 mmol) and cyclohexanone (98 mg, 1.00mmol) dissolved in 5% AcOH/MeOH (5 ml) and stir at ambient temperaturefor 16 hours. Concentrate the reaction mixture and redissolved in EtOAc.Wash the EtOAc solution with 5% aq. KOH and brine before drying (MgSO₄)and concentrating. Purify on silica gel (5% (1N NH₃/MeOH)/DCM) to obtain145 mg of the title compound as a white foam. Mass spectrum (ion spray):m/z=380 (M+1); ¹HNMR (CDCl₃): 8.56 (s, 1H), 8.15 (d, 1H), 7.22-7.14 (m,2H), 6.90 (m, 2H), 5.79 (br. s, 2H), 2.99 (m, 1H), 2.96-2.79 (m, 2H),2.63-2.41 (m, 3H), 1.91 (m, 2H), 1.85-1.67 (m, 6H), 1.31-1.04 (m, 6H).

Example 2056-(5-Cyclopentylaminomethyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide

Using a method similar to Example 204, using6-(5-aminomethyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide(intermediate 20, 297 mg, 1.00 mmol), cyclopentanone (168 mg, 2.00mmol), and NaBH₃CN (125 mg, 2.00 mmol) gives the title compound (137 mg)as a white foam. Mass spectrum (ion spray): m/z=366 (M+1); ¹HNMR(CDCl₃): 8.56 (s, 1H), 8.15 (d, 1H), 7.22-7.15 (m 2H), 6.93-4.89 (m,2H), 5.82 (br. s, 2H), 3.11 (m, 1H), 3.02 (m, 1H), 2.92-2.78 (m, 2H),2.63-2.42 (m, 2H), 1.91-1.50 (m, 10H), 1.35 (m, 2H).

Example 2066-[5-(Isopropylamino-methyl)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-nicotinamide

Using a method similar to Example 204, using6-S-aminomethyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide(intermediate 20,297 mg, 1.00 mmol), acetone (116 mg, 2.00 mmol), andNaBH₃CN (125 mg, 2.00 mmol) gives the title compound (139 mg) as a whitefoam. Mass spectrum (ion spray): m/z=340 (M+1); ¹HNMR (CDCl₃): 8.57 (s,1H), 8.13 (d, 1H), 7.21-7.13 (m, 2H), 6.90-6.87 (m, 2H), 6.27 (br. s,2H), 2.97 (m, 1H), 2.91-2.75 (m, 3H), 2.62-2.41 (m, 2H), 1.83-1.63 (m,4H), 1.07 (d, 6H).

Example 2076-{5-[(Tetrahydro-pyran-4-ylamino)methyl]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-nicotinamide

Using a method similar to Example 204, using6-(5-aminomethyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)nicotinamide(intermediate 20, 238 mg, 0.800 mmol), tetrahydro-4H-pyran-4-one (160mg, 1.60 mmol), and NaBH₃CN (100 mg, 1.60 mmol) gives the title compound(138 mg) as a white foam. Mass spectrum (ion spray): m/z=382 (M+1);¹HNMR (CDCl₃): 8.57 (s, 1H), 8.16 (d, 1H), 7.23-7.16 (m, 2H), 6.94-6.90(m, 2H), 5.86 (br. s, 2H), 4.00 (d, 2H), 3.40 (t, 2H), 3.15-2.78 (m,3H), 2.65-2.41 (m, 2H), 1.97-1.46 (m, 9H).

Example 2086-{5-[(4-Methyl-pentylamino)-methyl]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-nicotinamide

Add NaH (60% oil suspension, 30 mg, 0.750 mmol) to a solution of[5-(5-cyanopyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-carbamicacid tert-butyl ester (Intermediate 22, 189 mg, 0.500 mmol) and DMF (5ml) stirring at ambient temperature under nitrogen. After 20 minutes,add 1-bromo-4-methylpentane (247 mg, 1.50 mmol) and beat the mixture at60° C. overnight. After cooling, pour the mixture into water and extractwith EtOAc (2×). Wash the extract with water and brine before drying((MgSO₄) and concentrating. Purify on silica gel (20% EtOAc/Hexane) toobtain 111 mg of[5-(5-cyano-pyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-(4-methyl-pentyl)carbamicacid tert-butyl ester as a colorless glass.

Add 30% aq. H₂O₂ (239 uL) to a suspension of[5-(5-cyano-pyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-(4-methyl-pentyl)-carbamicacid tert-butyl ester (111 mg, 0.239 mmol), K₂CO₃ (16 mg, 0.120 mmol)and DMSO (3 ml) stirring in an ice/water bath. After 1.5 hours, pour thereaction mixture into water and extract with EtOAc. Wash the extractwith water and brine before drying (MgSO₄) and concentrating to give[5-(5-Carbamoyl-pyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-(4methyl-pentyl)-carbamic acid tert-butyl ester (114 mg) as a white foam.Use this material without further purification.

Add TFA (540 mg, 4.73 mmol) to a solution of[5-(5-Carbamoyl-pyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-(4-methyl-pentyl)-carbamicacid tert-butyl ester (114 mg, 0.236 mmol) and DCM (3 ml) stirring undernitrogen at ambient temperature. After 18 hours, concentrate themixture, redissolve in EtOAc and wash with 1M aq. K₂CO₃, water, andbrine. Dry (MgSO₄), concentrate, and purify on silica gel (5% (1NNH₃/MeOH)/DCM) to obtain the title compound (80 mg) as an off-whitesolid. Mass spectrum (ion spray): m/z=382 (M+1); ¹HNMR (CDCl₃): 8.56 (s,1H), 8.15 (d, 1H), 7.21-7.13 (m, 2H), 6.90 (m, 2H); 6.04 (br. s, 2H),3.01 (m, 1H), 2.90-2.79 (m, 2H), 2.68-2.55 (m, 3H), 2.49-2.41 (m, 1H),1.84-1.64 (m, 4H), 1.57-1.46 (m, 3H), 1.19 (m, 2H), 0.87 (d, 6H).

Example 2096-{5-[(2-Cyclopropyl-ethylamino)-methyl]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-nicotinamide

Using a method similar to Example 208, using[5-(5-cyano-pyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-carbamicacid tert-butyl ester (Intermediate 22, 379 mg, 1.00 mmol),toluene-4-sulfonic acid 2-cyclopropyl-ethyl ester (Tetrahedron (1986),42(4), 1093-108, 721 mg, 3.00 mmol), and NaH (60% oil suspension, 80 mg,2.00 mmol) gives the title compound (135 mg) as a white foam. Massspectrum (ion spray): m/z=366 (M+1); ¹HNMR (CDCl₃): 8.56 (s, 1H), 8.15(d, 1H), 7.23-7.15 (m, 2H), 6.92 (m, 2H), 5.77 (br. s, 2H), 3.05 (m,1H), 2.94-2.74 (m, 4H), 2.64-2.43 (m, 2H), 1.87-1.58 (m, 4H), 1.44 (m,2H), 0.68 (m, 1H), 0.44 (m, 2H), 0.07 (m, 2H).

Example 2104-{1-[2-(3-Fluoro-phenyl)-ethylamino]-indan-5-yloxy}-benzamide

In a round bottom flask, combine 4-(1-Oxo-indan-5-yloxy)-benzamide(Intermediate 24, 45.0 mg, 0.17 mmol), m-Fluorophenethylamine (33 uL,0.25 mmol), THF (5 mL), and Ti(OiPr)₄ (0.1 mL, 0.27 mmol) at 0° C. undernitrogen atmosphere. Stir the reaction for 3 hours then add TiCl₄ (0.3mL, 0.27 mmol) at 0° C. For the next 2 hours, warm the reaction to roomtemperature and then add BH₃SMe₂ (0.09 mL, 0.17 mmol). Stir the reactionat room temperature for 12 hours, then add 1N NaOH (aq) and stir for 2hours. Centrifuge and decant the reaction into a separatory funnel andwash the organic phase with water and dry over Na₂SO₄. Concentrate thereaction under reduced pressure and purify using reverse phasechromatography (5% to 95% 0.001% TFA buffer in acetonitrile/water) toafford 3.5 mg, 0.01 mmol (6% yield) of the title compound:

Example 211 4-(1-Phenethylamino-indan-5-yloxy)benzamide

Using a method similar to Example 210, using Phenethylamine (32 uL, 0.25mmol) gives 4.0 mg (6% yield) of the title compound.

Example 2124-(5-Benzylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-benzamide

Combine 4-(5-Oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-benzamide(Intermediate 26, 120.0 mg, 0.43 mmol), Benzylamine (70 uL, 0.64 mmol),THF (3 mL), and Ti(OiPr) (0.2 mL, 0.68 mmol) at 0° C. Stir the reactionfor 12 hours allowing it to come to room temperature and then add TiCl₄(0.7 mL, 0.68 mmol) at 0° C. After reaction stirs for 3 hours, addBH₃SMe₂ at room temperature. After the reaction stirs for 72 hours, add1N NaOH aq (6 mL) at room temperature. Upon addition, a precipitateforms. Allow the reaction to stir for an additions 12 hours, centrifuge,and decant off aqueous and organic layers. Separate the organic layerand concentrate. Add the organic mixture to a 2 g SCX column, wash withMeOH, and elute with 1N NH₃ MeOH. Purify using reverse phasechromatography (5% to 95% 0.001% TFA buffer in acetonitrile/water) toafford 19.4 mg, 0.05 mmol (12% yield) of the title compound: ¹H NMR (500MHz, CDCl₃); 1.7-1.8 (2H, m), 1.9-2.1 (3H, m), 2.6-2.9 (2H, m), 3.8-4.0(3H, m), 6.7-6.9 (2H, m), 6.9-7.0 (2H, m), 7.2-7.5 (6H, m), 7.7-7.9 (2H,m); MS m/z 284 (M of SM+3).

Example 2134-{5-[2-(3-Fluoro-phenyl)-ethylamino]-5,6,7,8-tetrahydro-naphthalen-2-yloxy}-benzamide

Using a method similar to Example 212, using m-Fluorophenethylamine (84uL, 0.64 mmol) gives 26.5 mg (15% yield) of the title compound: ¹H NMR(500 MHz, CDCl₃); 1.6-1.8 (1H, m), 1.8-2.0 (3H, m), 2.5-3.0 (6H, m),3.7-3.8 (1H, m), 5.6-6.1 (2H, br d), 6.6-7.0 (7H, m), 7.1-7.3 (2H, m),7.7-7.9 (2H, m); MS m/z 250 (M of SM+3).

Example 2144-[5-(3-Methyl-butylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-benzamide

Using a method similar to Example 212, using Isoamylamine (74 uL, 0.64mmol) gives 45.0 mg (30% yield) of the title compound: ¹H NMR (500 MHz,CDCl₃); 0.8-1.0 (6H, m), 1.3-1.5 (2H, m), 1.5-1.8 (2H, m), 1.8-2.0 (3H,m), 2.6-2.8 (4H, m), 3.7-3.8 (1H, m), 5.8-6.2 (2H, br s), 6.7-6.9 (2H,m), 6.9-7.0 (2H, m), 7.2-7.4 (1H, m), 7.7-7.8 (2H, m); MS m/z 353 (M+1)and 284 (M of SM+3).

Example 2154-(5-Phenethylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-benzamide

Using a method similar to Example 212, using Phenethylamine (80 uL, 0.64mmol) gives 21.7 mg (13% yield) of the title compound: ¹H NMR (500 MHz,CDCl₃); 1.5-2.2 (5H, m), 2.5-3.1 (6H, m), 3.2-3.4 (1H, m), 3.7-3.9 (1H,m), 6.7-6.9 (2H, m), 6.9-7.1 (2H, m), 7.1-7.4 (6H, m), 7.7-7.9 (2H, m);MS m/z 284 (M of SM+3).

Example 2164-(5-Pentylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-benzamide

Using a method similar to Example 212, using Pentylamine (75 uL, 0.64mmol) gives 73.6 mg (49% yield) of the tide compound: ¹H NMR (500 MHz,CDCl₃); 0.8-1.0 (3H, m), 1.2-1.4 (4H, m), 1.4-1.6 (2H, m), 1.6-1.8 (1H,m), 1.8-2.0 (3H, m), 2.6-2.9 (4H, m), 3.7-3.8 (1H, m), 6.1-6.4 (2H, brs), 6.7-6.9 (2H, m), 6.9-7.1 (2H, m), 7.2-7.4 (1H, m), 7.7-7.9 (2H, m);MS m/z 284 (M of SM+3).

Example 2174-[5-(4-Methyl-cyclohexylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-benzamide

Using a method similar to Example 212, using 4-Methylcyclohexylamine (85uL, 0.64 mmol) gives 95.0 mg (58% yield) of the title compound: ¹H NMR(500 MHz, CDCl₃); 0.9-1.2 (6H, m), 1.3-1.6 (4H, m), 1.6-2.0 (7H, m),2.6-3.0 (3H, m), 3.8-3.9 (1H, m), 6.2-6.4 (2H, br s), 6.7-7.0 (4H, m),7.3-7.4 (1H, m), 7.7-7.9 (2H, m); MS m/z 284 (M of SM+3).

Example 2186-[5-(2-Phenyl-propylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide

Prepared according to General Procedure IV using intermediate 2 and2-methylphenethylamine, to afford a 50% yield.

¹H NMR (MeOD-d₄) δ: 8.56 (d, 1H, J=2.4 Hz), 8.17 (dd, 1H, J=8.6, 2.4Hz), 7.40-7.10 (m, 5H), 7.02-6.75 (m, 4H), 3.80-3.90 (m, 1H), 3.00-2.90(m, 3H), 2.70-2.60 (m, 2H), 1.95-1.60 (m, 4H), 1.30 (m, 4H).

¹³C NMR (MeOD-d₄) δ: 167.2, 164.8, 164.7, 151.2, 151.1, 146.4, 143.9,143.8, 138.5, 138.4, 138.3, 134.3, 134.2, 128.7, 128.4, 127.4, 126.0,125.9, 125.3, 123.6, 120.1, 119.9, 117.4, 117.3, 109.3, 54.1, 53.0,52.8, 51.5, 38.9, 38.5, 28.0, 27.9, 26.6, 26.2, 18.4, 18.3, 17.6, 17.3.

MS (Electrospray): 402.2 (M⁺+1).

Example 2196-[5-(2-Hydroxy-2-phenyl-ethylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide

To a solution of the silyl derivative (Intermediate 34) in THF asolution 1M of tetrabutylammonium fluoride is added. The resultingsolution is stirred overnight. Water and ethyl acetate is added. Theaqueous layer is extracted with additional ethyl acetate. The combinedorganic phase was dried and evaporated to yield a crude which waspurified by column chromatography.

98% Yield.

¹H NMR (MeOD-d₄) δ: 8.56 (d, 1H, J=2.4 Hz), 8.17 (dd, 1H, J=8.5, 2.4Hz), 7.55-7.25 (m, 6H), 7.02-6.80 (m, 31), 4.00-3.80 (m, 1H), 3.00-2.60(m, 4H), 2.00-1.60 (m, 6H).

¹³C NMR (MeOD-d₄) δ: 168.1, 165.7, 152.2, 147.3, 143.2, 139.5, 139.3,135.1, 129.7, 127.9, 127.1, 125.6, 124.5, 121.0, 120.9, 118.4, 110.3,72.6, 71.8, 54.9, 54.4, 53.9, 53.5, 28.9, 27.7, 27.5, 18.4, 18.2.

MS (Electrospray): 404.2 (M⁺+1).

Example 2206-(6-Benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy)-nicotinamide

A solution of Intermediate 37 (30 mg, 0.08 mmol) in DMSO (0.5 mL) istreated with K₂CO₃ (15 mg, 0.11 mmol) and 6-chloronicotinamide (13 mg,0.08 mmol). The reaction mixture is heated to 100° C. for 6 hours, thencooled to room temperature and poured into 25 mL CH₂Cl₂. The organicsare washed with 25 mL water, 25 mL brine, then dried over MgSO₄ andevaporated to give 30 mg crude material. This material is partiallypurified by flash chromatography using 2:1 ethyl acetate/hexanes assolvent to give 8 mg of product contaminated with 6-chloronicotinamide.The product was dissolved in 1 mL CH₂Cl₂ and treated with 20 uL oftrifluoroacetic acid. After 2 hours, an additional 20 uL oftrifluoroacetic acid was added and the reaction was stirred overnight.The reaction mixture was then diluted with methanol and poured onto a500 mg strong cation exchange column. The column was washed withmethanol, and the product was eluted with 2N ammonia/methanol.Evaporation of the eluent gave 4.5 mg final product, or 14% yield fromintermediate 37.

Example 2216-(6-Phenethylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy)-nicotinamide

The compound is prepared analogously to example 220 starting fromintermediate 38 to give 6.7 mg product, 21% yield.

Example 222 6-[2-(2-Cyclohexyl-ethylamino)-indan-5-yloxy]-nicotinamide

The above compound is prepared according to general Procedure V usingIntermediate 15 and cyclohexane-acetaldehyde.

MS ES⁺ (M+H)⁺ 380.

¹H-NMR (CDCl₃, 400 MHz): 8.55 (d, J=2.44 Hz, 1H), 8.15 (dd, 1H, J=7.8,2.44 Hz), 7.20 (d, J=8.3 Hz, 1H), 6.87-6.94 (m, 3H), 3.67 (p, J=6.84 Hz,1H), 3.17 (m, 2H), 2.66-2.83 (m, 4H), 0.89-1.69 (m, 13H).

Example 223 6-[2-(2-Cyclopentyl-ethylamino)-indan-5-yloxy]-nicotinamide

The above compound is prepared according to General Procedure V usingIntermediate 15 and cyclopentane-acetaldehyde.

MS ES⁺ (M+H)⁺.

¹H-NMR (CDCl₃, 400 MHz): 8.57 (d, J=2.44 Hz, 1H), 8.15 (dd, 1H J=2.44,8.30 Hz), 7.20 (d, J=8.3 Hz, 1H), 6.88-6.95 (m, 3H), 3.68 (m, 1H), 3.18(m, 2H), 2.66-2.84 (m, 4H); 1.30-1.79 (m, 1H).

Examples 224-246

Mass General (pos. Example Serial # IUPAC name Procedure Intermediate #Reagent ion) 224 2073577 6-[2- V 15 cyclopropane 342 (Cyclopropylmethyl-carboxaldehyde amino)-indan-5- yloxy]-nicotinamide 225 20735786-(2-Isobutylamino- V 15 isobutyraldehyde 326 indan-5-yloxy)-nicotinamide 226 2073579 6-(2-Butylamino- V 15 butyraldehyde 326indan-5-yloxy)- nicotinamide 227 2073580 6-[2-(2-Methyl- V 152-methylbutyraldehyde 340 butylamino)-indan- 5-yloxy]- nicotinamide 2282073581 6-[2-(3-Hydroxy- V 15 3- 342 butylamino)-indan-hydroxybutyraldehyde 5-yloxy]- nicotinamide 229 2073582 6-[2- V 15cyclopentane 352 (Cyclopentylmethyl- carboxaldehyde amino)-indan-5-yloxy]-nicotinamide 230 2073583 6-[2-(2-Ethyl- V 15 2-ethylbutyraldehyde354 butylamino)-indan- 5-yloxy]- nicotinamide 231 20735846-[2-(2-Methyl- V 15 2-methylpentanal 354 pentylamino)-indan- 5-yloxy]-nicotinamide 232 2073585 6-(2-Hexylamino- V 15 hexanal 354indan-5-yloxy)- nicotinamide 233 2073586 6-[2-(5-Hydroxy- V 155-hydroxypnetanal 356 pentylamino)-indan- 5-yloxy]- nicotinamide 2342073588 6-{2-[(Cyclohex-3- V 15 3-cyclohexene-1- 364 enylmethyl)-amino]-carboxaldehyde indan-5-yloxy}- nicotinamide 235 2073590 6-[2- V 15cyclohexane 366 (Cyclohexylmethyl- carboxaldehyde amino)-indan-5-yloxy]-nicotinamide 236 2073592 6-{2- V 15 norbornen-5-al 376[(Bicyclo[2.2.1]hept- 5-en-2-ylmethyl)- amino]-indan-5-yloxy}-nicotinamide 237 2073593 6-[2-(4,4,4- V 15 4,4,4- 380 Trifluoro-trifluorobutyraldehyde butylamino)-indan- 5-yloxy]- nicotinamide 2382073594 6-[2-(3,5,5- V 15 3,5,5-trimethylhexanal 396 Trimethyl-hexylamino)-indan- 5-yloxy]- nicotinamide 239 2073595 6-[2-(3-Phenyl- V15 3-methyl-3-phenyl- 402 butylamino)-indan- propionaldehyde 5-yloxy]-nicotinamide 240 2073596 6-[2-(2-Benzyloxy- V 15 benzyloxyacetaldehyde404 ethylamino)-indan- 5-yloxy]- nicotinamide 241 20735986-{2-[3-(5-Methyl- V 15 3-(5-methyl-2-furyl)- 406 furan-2-yl)-butyraldehyde butylamino]-indan- 5-yloxy}- nicotinamide 242 20736006-(2-Decylamino- V 15 decanal 410 indan-5-yloxy)- nicotinamide 2432073601 6-{2-[3-(4- V 15 3-(4-isopropylphenyl)- 444 Isopropyl-phenyl)-2-isobutyraldehyde methyl- propylamino]-indan- 5-yloxy}- nicotinamide 2442073603 6-[2-(3- V 15 2-methyl-3-(3,4- 446 Benzo[1,3]dioxol-5-methylenedioxyphenyl)- yl-2-methyl- propanal propylamino)-indan-5-yloxy]- nicotinamide 245 2073605 6-[2-(2,2-Diphenyl- V 15diphenyl-acetaldehyde 450 ethylamino)-indan- 5-yloxy]- nicotinamide 2462076993 6-[2-(2-Cyclohexyl- V 15 cyclohexyl- 380 ethylamino)-indan-acetaldehyde 5-yloxy]- nicotinamide

Example 2476-{2-[(3-Methyl-butylamino)-methyl]-indan-5-yloxy}-nicotinamide

Combine 6-(2-Formyl-indan-5-yloxy)-nicotinamide (Intermediate 32, 25.3mg, 0.09 mmol), MeOH (2.4 mL), trimethylorthoformate (1.6 mL), andisopentyl amine (9 uL, 0.08 mmol). After the reaction stirs at roomtemperature under a nitrogen atmosphere for 4.5 hours, add NaBH (4.1 mg,0.11 mmol), then stir at room temperature for another 12 hours. Afterthat time, concentrate under reduced pressure then add ethyl acetate.Wash the organic phase with water, brine, and dry over Na₂SO₄. Afterconcentration under reduced pressure the mixture, add to a 2 g SCXcolumn, wash with MeOH and elute with 1N NH₃-MeOH. After concentration,flash chromatograph using 2% 1N NH₃-MeOH, 20% THF, 38% DCM to afford 7.0mg, 0.02 mmol (25% yield) of the title compound: ¹H NMR (500 MHz,d-Methanol); 0.9 (6 d), 1.4-1.5 (2H, m), 1.6-1.7 (1H, m), 2.6-2.8 (6H,m), 3.1-3.2 (2H, m), 3.3-3.4 (1H, m), 6.8 (1H, d), 6.9 (1H, s), 7.1 (1H,d), 7.2 (1H, d), 8.1 (1H, d), 8.5 (1H, s); TLC 2% in NH₃-MeOH:20%THF:78% CH₂Cl₂:R_(f)=0.27.

Example 248 6-[2-(3-Phenethylamino-methyl)-indan-5-yloxy]-nicotinamide

Using a method similar to Example 247, using Phenethylamine (20 uL, 0.16mmol) gives 17.0 mg (27% yield) of the title compound: ¹H NMR (500 MHz,CDCl₃); 2.6-3.2 (12H, d), 6.8-7.0 (3H, m), 7.1-7.4 (7H, m), 7.9 (1H, d),8.5 (1H, s); TLC 2% 1N NH₃-MeOH:20% THF:78% CH₂Cl₂:R_(f)=0.31.

Example 249 6-[2-(Benzylamino)-methyl]-indan-5-yloxy]-nicotinamide

Using a method similar to Example 247, using Benzylamine (22 uL, 0.20mmol) gives 41.7 mg (56% yield) of the title compound: ¹H NMR (500 MHz,CDCl₃); 2.6-2.8 (5H, m), 3.0-3.2 (2H, m), 3.8 (2H, s), 6.8-7.0 (3H, m),7.2-7.4 (6H, m), 7.9 (1H, d), 8.5 (1H, s); TLC 2% 1N NH₃-MeOH:200%THF:78% CH₂Cl₂:R_(f)=0.43

1-11. (canceled)
 12. A pharmaceutical composition comprising a compoundof claim 14 in association with a carrier, diluent and/or excipient. 13.(canceled)
 14. A compound selected from:6-{5-[2-(3-Fluoro-phenyl)-ethylamino]-5,6,7,8-tetrahydro-naphthalen-2-yloxy}-nicotinamide,6-{5-[2-(3-Fluoro-phenyl)-ethylamino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-nicotinamide,6-{3-[2-(3-Fluoro-phenyl)-ethylamino]-indan-5-yloxy}-nicotinamide,6-{1-[2-(3-Fluoro-phenyl)-ethylamino]-indan-5-yloxy}-nicotinamide,6-{1-[2-(3-Fluoro-phenyl)-ethylamino]-indan-4-yloxy}-nicotinamide,6-[8-(3-Methyl-butylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,6-[5-(3-Methyl-butylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,6-[5-(3-Methyl-butylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-nicotinamide,6-[8-(4-Methyl-cyclohexylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,6-[5-(4-Methyl-cyclohexylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,6-[5-(4-Methyl-cyclohexylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-nicotinamide,6-[1-(4-Methyl-cyclohexylamino)-indan-5-yloxy]-nicotinamide,6-[1-(4-Methyl-cyclohexylamino)-indan-4-yloxy]-nicotinamide,6-(7-Pentylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide,6-(6-Pentylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide,6-(6-Pentylamino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide,6-(7-Pentylamino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide,6-(7-Benzylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide,6-(6-Benzylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide,6-(6-Benzylamino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide,6-(7-Benzylamino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide,6-(7-Phenethylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide,6-(6-Phenethylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide,6-(6-Phenethylamino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide,6-(7-Phenethylamino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide,6-{7-[2-(3-Fluoro-phenyl)-ethylamino]-5,6,7,8-tetrahydro-naphthalen-2-yloxy}-nicotinamide,6-{6-[2-(3-Fluoro-phenyl)-ethylamino]-5,6,7,8-tetrahydro-naphthalen-2-yloxy}-nicotinamide,6-{6-[2-(3-Fluoro-phenyl)-ethylamino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-nicotinamide,6-{7-[2-(3-Fluoro-phenyl)-ethylamino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-nicotinamide,6-[7-(3-Methyl-butylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,6-[6-(3-Methyl-butylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,6-[6-(3-Methyl-butylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-nicotinamide,6-[7-(3-Methyl-butylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-nicotinamide,6-[7-(4-Methyl-cyclohexylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,6-[6-(4-Methyl-cyclohexylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-nicotinamide,6-[7-(4-Methyl-cyclohexylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-nicotinamide,6-[7-(3-Phenyl-propylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,6-[6-(3-Phenyl-propylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,6-[6-(3-Phenyl-propylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-nicotinamide,6-[7-(3-Phenyl-propylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-nicotinamide,6-[5-(2-Methylsulfanyl-ethylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,6-[1-(2-Methylsulfanyl-ethylamino)-indan-5-yloxy]-nicotinamide,6-{5-[2-(3-Methoxy-phenyl)-ethylamino]-5,6,7,8-tetrahydro-naphthalen-2-yloxy}-nicotinamide,6-{1-[2-(3-Methoxy-phenyl)-ethylamino]-indan-5-yloxy}-nicotinamide,6-[5-(2-Dimethylamino-ethylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,6-[1-(2-Dimethylamino-ethylamino)-indan-5-yloxy]-nicotinamide,6-[5-(2-Pyrrolidin-1-yl-ethylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,6-[1-(2-Pyrrolidin-1-yl-ethylamino)-indan-5-yloxy]-nicotinamide,6-[5-(2-Pyridin-2-yl-ethylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,6-[1-(2-Pyridin-2-yl-ethylamino)-indan-5-yloxy]-nicotinamide,6-[5-(2-Morpholin-4-yl-ethylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,6-[1-(2-Morpholin-4-yl-ethylamino)-indan-5-yloxy]-nicotinamide,6-[1-(1,2-Diphenyl-ethylamino)-indan-5-yloxy]-nicotinamide,6-{5-[2-(4-Fluoro-phenyl)-ethylamino]-5,6,7,8-tetrahydro-naphthalen-2-yloxy}-nicotinamide,6-{1-[2-(4-Fluoro-phenyl)-ethylamino]-indan-5-yloxy}-nicotinamide,6-[5-(2-Acetylamino-ethylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,6-[1-(2-Acetylamino-ethylamino)-indan-5-yloxy]-nicotinamide,6-{5-[2-(5-Fluoro-1H-indol-3-yl)-ethylamino]-5,6,7,8-tetrahydro-naphthalen-2-yloxy}-nicotinamide,6-{1-[2-(5-Fluoro-1H-indol-3-yl)-ethylamino]-indan-5-yloxy}-nicotinamide,3-[6-(5-Carbamoyl-pyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylamino]-propionicacid isopropyl ester,3-[5-(5-Carbamoyl-pyridin-2-yloxy)-indan-1-ylamino]-propionic acidisopropyl ester, 6-(2-Pentylamino-indan-5-yloxy)-nicotinamide,6-(2-Pentylamino-indan-4-yloxy)-nicotinamide,6-(2-Benzylamino-indan-5-yloxy)-nicotinamide,6-(2-Benzylamino-indan-4-yloxy)-nicotinamide,6-[2-(3-Phenyl-propylamino)-indan-5-yloxy]-nicotinamide,6-[2-(3-Phenyl-propylamino)-indan-4-yloxy]-nicotinamide,6-[2-(3-Methyl-butylamino)-indan-5-yloxy]-nicotinamide,6-[2-(3-Methyl-butylamino)-indan-4-yloxy]-nicotinamide,6-[2-(2-Phenyl-propylamino)-indan-5-yloxy]-nicotinamide,6-[2-(2-Phenyl-propylamino)-indan-4-yloxy]-nicotinamide,6-(2-Phenethylamino-indan-5-yloxy)-nicotinamide,6-(2-Phenethylamino-indan-4-yloxy)-nicotinamide,6-{2-[(5-Fluoro-1H-indol-3-ylmethyl)-amino]-indan-5-yloxy}-nicotinamide,6-{2-[(5-Fluoro-1H-indol-3-ylmethyl)-amino]-indan-4-yloxy}-nicotinamide,6-[2-(3-Dimethylamino-2,2-dimethyl-propylamino)-indan-5-yloxy]-nicotinamide,6-[2-(3-Dimethylamino-2,2-dimethyl-propylamino)-indan-4-yloxy]-nicotinamide,6-{5-[(Benzo[b]thiophen-3-ylmethyl)-amino]-5,6,7,8-tetrahydro-naphthalen-2-yloxy}-nicotinamide,6-{1-[(Benzo[b]thiophen-3-ylmethyl)-amino]-indan-5-yloxy}-nicotinamide,6-[5-(2-Methoxy-ethylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,6-[1-(2-Methoxy-ethylamino)-indan-5-yloxy]-nicotinamide,6-{5-[2-(3-Trifluoromethyl-phenyl)-ethylamino]-5,6,7,8-tetrahydro-naphthalen-2-yloxy}-nicotinamide,6-{1-[2-(3-Trifluoromethyl-phenyl)-ethylamino]-indan-5-yloxy}-nicotinamide,6-[5-(2-m-Tolyl-ethylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,6-{5-[2-(4-Fluoro-phenyl)-1,1-dimethyl-ethylamino]-5,6,7,8-tetrahydro-naphthalen-2-yloxy}-nicotinamide,6-{1-[2-(4-Fluoro-phenyl)-1,1-dimethyl-ethylamino]-indan-5-yloxy}-nicotinamide,6-[5-(3-Hydroxy-propylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,6-[1-(3-Hydroxy-propylamino)-indan-5-yloxy]-nicotinamide,6-[5-(2,2,2-Trifluoro-ethylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,6-[1-(2,2,2-Trifluoro-ethylamino)-indan-5-yloxy]-nicotinamide,6-[5-(2,2-Diphenyl-ethylamino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,6-[5-(4-Phenyl-piperidin-1-yl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,6-[1-(4-Phenyl-piperidin-1-yl)-indan-5-yloxy]-nicotinamide,6-[5-(Benzyl-methyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,6-[1-(Benzyl-methyl-amino)-indan-5-yloxy]-nicotinamide,6-[5-(3,4-Dihydro-1H-isoquinolin-2-yl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,6-[1-(3,4-Dihydro-1H-isoquinolin-2-yl)-indan-5-yloxy]-nicotinamide,6-(5-Thiomorpholin-4-yl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide,6-(1-Thiomorpholin-4-yl-indan-5-yloxy)-nicotinamide,2-[6-(5-Carbamoyl-pyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-1,2,3,4-tetrahydro-isoquinoline-3-carboxylicacid tert-butylamide,2-[6-(5-Carbamoyl-pyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-1,2,3,4-tetrahydro-isoquinoline-3-carboxylicacid tert-butylamide,6-[5-(5-Oxo-[1,4]diazepan-1-yl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,6-[1-(5-Oxo-[1,4]diazepan-1-yl)-indan-5-yloxy]-nicotinamide,6-[5-(Methyl-phenethyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,6-[1-(3-Acetylamino-pyrrolidin-1-yl)-indan-5-yloxy]-nicotinamide,6-[1-(3-Phenyl-piperidin-1-yl)-indan-5-yloxy]-nicotinamide,6-[1-(3-Phenyl-pyrrolidin-1-yl)-indan-5-yloxy]-nicotinamide,6-[1-(3-Propylamino-propylamino)-indan-5-yloxy]-nicotinamide,6-[1-(3,3-Dimethyl-butylamino)-indan-5-yloxy]-nicotinamide,6-(1-Decylamino-indan-5-yloxy)-nicotinamide,6-[1-(2-Ethyl-hexylamino)-indan-5-yloxy]-nicotinamide,6-{1-[(Tetrahydro-furan-2-ylmethyl)-amino]-indan-5-yloxy}-nicotinamide,6-(1-Cycloheptylamino-indan-5-yloxy)-nicotinamide,6-{1-[2-(1-Methyl-pyrrolidin-2-yl)-ethylamino]-indan-5-yloxy}-nicotinamide,6-(1-Cyclopropylamino-indan-5-yloxy)-nicotinamide,6-[1-(1,3-Dimethyl-butylamino)-indan-5-yloxy]-nicotinamide,6-(1-Cyclooctylamino-indan-5-yloxy)-nicotinamide,6-[1-(2,3-Dimethyl-cyclohexylamino)-indan-5-yloxy]-nicotinamide,6-(1-Cyclobutylamino-indan-5-yloxy)-nicotinamide,6-(1-Cyclopentylamino-indan-5-yloxy)-nicotinamide,6-[1-(Cyclohexylmethyl-amino)-indan-5-yloxy]-nicotinamide,6-{1-[(1-Ethyl-pyrrolidin-2-ylmethyl)-amino]-indan-5-yloxy}-nicotinamide,6-[1-(3-Cyclohexylamino-propylamino)-indan-5-yloxy]-nicotinamide,6-[1-(3-Methyl-cyclohexylamino)-indan-5-yloxy]-nicotinamide,6-(1-Cyclohexylamino-indan-5-yloxy)-nicotinamide,6-[1-(1-Isopropyl-2-methyl-propylamino)-indan-5-yloxy]-nicotinamide,6-[1-(2-Cyclohex-1-enyl-ethylamino)-indan-5-yloxy]-nicotinamide,6-[1-(2-Methyl-butylamino)-indan-5-yloxy]-nicotinamide,6-[1-(4-Hydroxy-cyclohexylamino)-indan-5-yloxy]-nicotinamide,6-[1-(1,4-Dimethyl-pentylamino)-indan-5-yloxy]-nicotinamide,6-[1-(1-Cyclohexyl-ethylamino)-indan-5-yloxy]-nicotinamide,6-[1-(3,3,5-Trimethyl-cyclohexylamino)-indan-5-yloxy]-nicotinamide,6-[1-(2-Carbamoyl-cyclohexylamino)-indan-5-yloxy]-nicotinamide,6-[1-(Cyclopropylmethyl-amino)-indan-5-yloxy]-nicotinamide,6-[1-(3-Butoxy-propylamino)-indan-5-yloxy]-nicotinamide,6-[1-(2,2,3,3,4,4,4-Heptafluoro-butylamino)-indan-5-yloxy]-nicotinamide,6-{1-[3-(2-Oxo-pyrrolidin-1-yl)-propylamino]-indan-5-yloxy}-nicotinamide,6-[1-(3-Azepan-1-yl-propylamino)-indan-5-yloxy]-nicotinamide,6-[1-(2,2,3,3,3-Pentafluoro-propylamino)-indan-5-yloxy]-nicotinamide,6-{1-[(2-Hydroxy-cyclooctylmethyl)-amino]-indan-5-yloxy}-nicotinamide,6-[1-(Bicyclohexyl-2-ylamino)-indan-5-yloxy]-nicotinamide,6-[1-(2-Hydroxy-cyclohexylamino)-indan-5-yloxy]-nicotinamide,6-{1-[2-(2-Methyl-cyclohexyl)-ethylamino]-indan-5-yloxy}-nicotinamide,6-{1-[2-(4-Methyl-cyclohexyl)-ethylamino]-indan-5-yloxy}-nicotinamide,6-[1-(2-Cyclopentyl-ethylamino)-indan-5-yloxy]-nicotinamide,6-[1-(Phenethylamino-methyl)-indan-5-yloxy]-nicotinamide,6-[8-(Phenethylamino-methyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,6-[3-(Phenethylamino-methyl)-indan-5-yloxy]-nicotinamide,6-[5-(Phenethylamino-methyl)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-nicotinamide,6-[1-(Benzylamino-methyl)-indan-5-yloxy]-nicotinamide,6-[8-(Benzylamino-methyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-nicotinamide,6-[3-(Benzylamino-methyl)-indan-5-yloxy]-nicotinamide,6-[5-(Benzylamino-methyl)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-nicotinamide,6-{1-[(3-Methyl-butylamino)-methyl]-indan-5-yloxy}-nicotinamide,6-{8-[(3-Methyl-butylamino)-methyl]-5,6,7,8-tetrahydro-naphthalen-2-yloxy}-nicotinamide,6-{3-[(3-Methyl-butylamino)-methyl]-indan-5-yloxy}-nicotinamide,6-{5-[(3-Methyl-butylamino)-methyl]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-nicotinamide,6-{1-[(2-Cyclohexyl-ethylamino)-methyl]-indan-5-yloxy}-nicotinamide,6-{8-[(2-Cyclohexyl-ethylamino)-methyl]-5,6,7,8-tetrahydro-naphthalen-2-yloxy}-nicotinamide,6-{5-[(2-Cyclohexyl-ethylamino)-methyl]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-nicotinamide,6-{1-[(Cyclohexylmethyl-amino)-methyl]-indan-5-yloxy}-nicotinamide,6-{8-[(Cyclohexylmethyl-amino)-methyl]-5,6,7,8-tetrahydro-naphthalen-2-yloxy}-nicotinamide,6-{3-[(Cyclohexylmethyl-amino)-methyl]-indan-5-yloxy}-nicotinamide,6-{5-[(Cyclohexylmethyl-amino)-methyl]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-nicotinamide,6-{1-[(2-Cyclopentyl-ethylamino)-methyl]-indan-5-yloxy}-nicotinamide, ora pharmaceutically acceptable salt thereof. 15-19. (canceled)